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WO2025085609A1 - Compositions de polymères de gélatine acryliques comprenant des cellules - Google Patents

Compositions de polymères de gélatine acryliques comprenant des cellules Download PDF

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Publication number
WO2025085609A1
WO2025085609A1 PCT/US2024/051735 US2024051735W WO2025085609A1 WO 2025085609 A1 WO2025085609 A1 WO 2025085609A1 US 2024051735 W US2024051735 W US 2024051735W WO 2025085609 A1 WO2025085609 A1 WO 2025085609A1
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Prior art keywords
polymer composition
kda
gelma
molecular weight
average molecular
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English (en)
Inventor
Max COTLER
Noel Vera-Gonzalez
Arthur Driscoll
Alex Chen
Athanasios SPEROS
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Gelmedix Inc
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Gelmedix Inc
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Publication of WO2025085609A1 publication Critical patent/WO2025085609A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/043—Mixtures of macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/78—Polymers containing oxygen of acrylic acid or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/26—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • the present disclosure provides improved acrylated gelatin polymer compositions, such as GelMA or GelAC polymer compositions.
  • the improved polymer compositions can be used for delivering one or more therapeutic agents, such as cells, to a target therapeutic area, such as the eye of a subject.
  • the improved polymer compositions are hydrogels which comprises gelatin methacryloyl (i.e., GelMA), gelatin acryloyl (GelAC), gelatin glycidyl acrylate (GelGA), gelatin glycidyl methacrylate (GelGMA), or polymerically crosslinked derivatives thereof.
  • the present disclosure provides polymer compositions which comprise at least one chemically modified gelatin.
  • the polymer composition comprises at least one acrylated gelatin.
  • the polymer composition comprises from about 0.5% to about 15.0% w/v of chemically modified gelatin.
  • the polymer composition comprises from about 0.5% to about 15.0% w/v of acrylated gelatin.
  • the polymer composition comprises at least one chemically modified gelatin (optionally an acrylated gelatin) and at least one polymer crosslinking initiator (e.g., photoinitiator).
  • the polymer composition comprises: (i) at least one chemically modified gelatin (optionally an acrylated gelatin); (ii) at least one polymer crosslinking initiator; and (iii) a population of cells.
  • the polymer composition comprises: (i) at least one acrylated gelatin; (ii) at least one polymer crosslinking initiator; and (iii) a population of cells.
  • the polymer composition is a precursor polymer composition.
  • the polymer composition is a gel polymer composition.
  • the polymer composition comprises from about 5 million cells/mL to about 20 million cells/mL of the cells. In certain embodiments, the polymer composition comprises from about 10 million cells/mL to about 15 million cells/mL of the cells. In certain embodiments, the polymer composition comprises about 10 million cells/mL or about 15 million cells/mL of the cells.
  • the polymer composition comprises at least one crosslinking initiator.
  • the crosslinking initiator comprises one or more light-activated photo-initiators, optionally one or more photo-initiators activated by visible light.
  • the polymer crosslinking initiator comprises eosin Y, N-vinylcaprolactam, triethanolamine, or any combination thereof.
  • the polymer crosslinking initiator comprises eosin Y disodium salt (EYDS), N- vinylcaprolactam (NVC), triethanolamine, or any combination thereof.
  • the polymer crosslinking initiator comprises eosin Y or eosin Y disodium salt (EYDS), N-Vinylpyrrolidone (NVP), triethanolamine, or any combination thereof.
  • the polymer crosslinking initiator comprises eosin Y or eosin Y disodium salt (EYDS), methylene bisacrylamide (MBA), triethanolamine, or any combination thereof.
  • the polymer crosslinking initiator comprises: (i) about 50 pM eosin Y or eosin Y disodium salt (EYDS); (ii) from about 1.0 to about 5.0 pL/mL ofN- vinylcaprolactam (NVC) or N-Vinylpyrrolidone (NVP); and (iii) triethanolamine.
  • the polymer crosslinking initiator comprises: (i) about 50 pM eosin Y disodium salt (EYDS); (ii) about 5.0 pL/mL N-Vinylpyrrolidone (NVP); and (iii) about 1.5% v/v of triethanolamine.
  • the polymer crosslinking initiator comprises: (i) about 50 pM eosin Y or eosin Y disodium salt (EYDS); (ii) from about 0.2% to about 0.3% methylene bisacrylamide (MBA); and (iii) triethanolamine.
  • the polymer crosslinking initiator comprises: (i) about 50 pM eosin Y disodium salt (EYDS); (ii) about 0.25% methylene bisacrylamide (MBA); and (iii) about 1.5% v/v of triethanolamine.
  • the chemically modified gelatin is an acrylated gelatin.
  • the polymer composition comprises from about 0.5% to about 15.0% w/v of at least one acrylated gelatin. In certain embodiments, the polymer composition comprises from about 1.0% to about 10.0% w/v of at least one acrylated gelatin. In certain embodiments, the polymer composition comprises from about 1.0% to about 5.0% w/v of at least one acrylated gelatin.
  • the acrylated gelatin has a degree of functionalization from about 10-80%. In certain embodiments, the acrylated gelatin has a degree of functionalization from 30-60%. In certain embodiments, the acrylated gelatin has a degree of functionalization of about 30%, about 45%, or about 60%.
  • the chemically modified gelatin comprises gelatin methacryloyl (GelMA).
  • the polymer composition comprises from about 0.5% to about 15.0% w/v of GelMA. In certain embodiments, the polymer composition comprises from about 2% to about 5.0% w/v of GelMA. In certain embodiments, the polymer composition comprises from about 2% to about 3.5% w/v of GelMA. In certain embodiments, the polymer composition comprises about 1.0% w/v of GelMA. In certain embodiments, the polymer composition comprises about 1.5% w/v of GelMA. In certain embodiments, the polymer composition comprises about 2.0% w/v of GelMA. In certain embodiments, the polymer composition comprises about 2.5% w/v of GelMA.
  • the polymer composition comprises about 3.0% w/v of GelMA. In certain embodiments, the polymer composition comprises about 3.5% w/v of GelMA. In certain embodiments, the polymer composition comprises about 4.0% w/v of GelMA. In certain embodiments, the polymer composition comprises about 4.5% w/v of GelMA. In certain embodiments, the polymer composition comprises about 5.0% w/v of GelMA.
  • At least a portion of the GelMA has a degree of methacrylation (DoM) from about 10-80%. In certain embodiments, at least a portion of the GelMA has a degree of methacrylation (DoM) from 40-60% DoM. In certain embodiments, at least a portion of the GelMA has a degree of methacrylation (DoM) of about 40%. In certain embodiments, at least a portion of the GelMA has a degree of methacrylation (DoM) of about 60% DoM.
  • DoM degree of methacrylation
  • the GelMA has a degree of methacrylation from about 10- 80%. In certain embodiments, the GelMA has a degree of methacrylation from 40-60%. In certain embodiments, the GelMA has a degree of methacrylation of about 40% or about 60%. [0016] In certain embodiments, at least a portion of the GelMA in the polymer composition has an average molecular weight from about 90 kDa to about 160 kDa. In certain embodiments, at least a portion of the GelMA in the polymer composition has an average molecular weight of about 90 kDa, about 138 kDa, or about 160 kDa.
  • At least a portion of the GelMA in the polymer composition has an average molecular weight of about 90. In certain embodiments, at least a portion of the GelMA in the polymer composition has an average molecular weight of about 160 kDa.
  • the GelMA in the polymer composition has an average molecular weight of about 90 kDa, about 138 kDa, or about 160 kDa. In certain embodiments, the GelMA in the polymer composition has an average molecular weight of about 90 kDa. In certain embodiments, the GelMA in the polymer composition has an average molecular weight of about 160 kDa.
  • At least a portion of the GelMA in the polymer composition has about 60% DoM and an average molecular weight from about 90-160 kDa. In certain embodiments, at least a portion of the GelMA in the polymer composition has about 60% DoM and an average molecular weight of about 90 kDa. In certain embodiments, at least a portion of the GelMA in the polymer composition has about 60% DoM and an average molecular weight of about 160 kDa.
  • At least a portion of the GelMA in the polymer composition has about 40% DoM and an average molecular weight from about 90-160 kDa. In certain embodiments, at least a portion of the GelMA in the polymer composition has about 40% DoM and an average molecular weight of about 90 kDa. In certain embodiments, at least a portion of the GelMA in the polymer composition has about 40% DoM and an average molecular weight of about 160 kDa.
  • At least a portion of the GelMA in the polymer composition has about 10% DoM and an average molecular weight from about 90-160 kDa. In certain embodiments, at least a portion of the GelMA in the polymer composition has about 10% DoM and an average molecular weight of about 90 kDa. In certain embodiments, at least a portion of the GelMA in the polymer composition has about 10% DoM and an average molecular weight of about 160 kDa.
  • the polymer composition comprises about 2.5% w/v of GelMA, having about 60% DoM and an average molecular weight of about 90 kDa. In certain embodiments, the polymer composition comprises about 2.0% w/v of GelMA, having about 60% DoM and an average molecular weight of about 90 kDa. In certain embodiments, the polymer composition comprises about 5.0% w/v of GelMA, having about 60% DoM and an average molecular weight of about 90 kDa. In certain embodiments, the polymer composition comprises about 5.0% w/v of GelMA, having about 40% DoM and an average molecular weight of about 160 kDa.
  • the polymer composition comprises about 1.0% w/v of GelMA, having about 10% DoM and an average molecular weight of about 160 kDa. In certain embodiments, the polymer composition comprises about 2.0% w/v of GelMA, having about 10% DoM and an average molecular weight of about 160 kDa. In certain embodiments, the polymer composition comprises about 1.0% of GelMA, having about 40% DoM and an average molecular weight of about 160 kDa. In certain embodiments, the polymer composition comprises about 1.0% of GelMA, having about 40% DoM and an average molecular weight of about 160 kDa about 2.5% of GelMA, having about 40% DoM and an average molecular weight of about 90 kDa.
  • the polymer composition comprises about 1.0% of GelMA, having about 40% DoM and an average molecular weight of about 160 kDa about 1.0% of GelMA, having about 40% DoM and an average molecular weight of about 160 kDa. In certain embodiments, the polymer composition comprises about 1.0% of GelMA, having about 40% DoM and an average molecular weight of about 160 kDa about 2.0% of GelMA, having about 40% DoM and an average molecular weight of about 90 kDa.
  • the polymer composition comprises any combination of (a) about 2.5% w/v of GelMA, having about 60% DoM and an average molecular weight of about 90 kDa; (b) about 2.0% w/v of GelMA, having about 60% DoM and an average molecular weight of about 90 kDa; (c) about 5.0% w/v of GelMA, having about 60% DoM and an average molecular weight of about 90 kDa; (d) about 5.0% w/v of GelMA, having about 40% DoM and an average molecular weight of about 160 kDa; (e) about 1.0% w/v of GelMA, having about 10% DoM and an average molecular weight of about 160 kDa; (f) about 2.0% w/v of GelMA, having about 10% DoM and an average molecular weight of about 160 kDa; (g) about 1.0% of GelMA, having about 40% DoM and an average molecular weight of about 160 kDa; (h) about
  • the polymer composition comprises a combination of a first GelMA mixture and a second GelMA mixture. In certain embodiments, the polymer composition comprises a combination of a first GelMA mixture and a second GelMA mixture, wherein the total GelMA in the polymer composition is from about 0.5% to about 5% w/v. In certain embodiments, the total GelMA in the polymer composition is from about 2% to about 5% w/v. In certain embodiments, the total GelMA in the polymer composition is from about 2% to about 4% w/v. In certain embodiments, total GelMA in the polymer composition is from about 3% to about 5% w/v. In certain embodiments, the total GelMA in the polymer composition is from about 3% to about 4% w/v. In certain embodiments, the total GelMA in the polymer composition is from about 3.5% w/v.
  • the polymer composition comprises: (a) GelMA which has about 60% DoM and an average molecular weight of about 90 kDa, and (b) GelMA which has about 10% DoM and an average molecular weight of about 160 kDa.
  • the polymer composition comprises: (a) about 2.5% w/v of GelMA, having about 60% DoM and an average molecular weight of about 90 kDa, and (b) about 1.0% w/v of GelMA, having about 10% DoM and an average molecular weight of about 160 kDa.
  • the polymer composition comprises: (a) GelMA which has about 40% DoM and an average molecular weight of about 90 kDa, and (b) GelMA which has about 40% DoM and an average molecular weight of about 160 kDa.
  • the polymer composition comprises: (a) GelMA which has about 40% DoM and an average molecular weight of about 90 kDa, and (b) GelMA which has about 40% DoM and an average molecular weight of about 160 kDa; wherein the ratio of GelMA which has about 40% DoM and an average molecular weight of about 90 kDa to GelMA which has about 40% DoM and an average molecular weight of about 160 kDa is about 7:3.
  • the polymer composition comprises: (a) GelMA which has about 40% DoM and an average molecular weight of about 90 kDa, and (b) GelMA which has about 40% DoM and an average molecular weight of about 160 kDa; wherein the ratio of GelMA which has about 40% DoM and an average molecular weight of about 90 kDa to GelMA which has about 40% DoM and an average molecular weight of about 160 kDa is about 7:3; and wherein the composition comprises about 2.5% w/v of GelMA.
  • the polymer composition comprises: (a) GelMA which has about 40% DoM and an average molecular weight of about 90 kDa, and (b) GelMA which has about 40% DoM and an average molecular weight of about 160 kDa; wherein the ratio of GelMA which has about 40% DoM and an average molecular weight of about 90 kDa to GelMA which has about 40% DoM and an average molecular weight of about 160 kDa is about 7:3; and wherein the composition comprises about 3.0% w/v of GelMA.
  • the polymer composition comprises: (a) GelMA which has about 40% DoM and an average molecular weight of about 90 kDa, and (b) GelMA which has about 40% DoM and an average molecular weight of about 160 kDa; wherein the ratio of GelMA which has about 40% DoM and an average molecular weight of about 90 kDa to GelMA which has about 40% DoM and an average molecular weight of about 160 kDa is about 7:3; and wherein the composition comprises about 3.5% w/v of GelMA.
  • the polymer composition comprises: (a) GelMA which has about 40% DoM and an average molecular weight of about 90 kDa, and (b) GelMA which has about 40% DoM and an average molecular weight of about 160 kDa; wherein the ratio of GelMA which has about 40% DoM and an average molecular weight of about 90 kDa to GelMA which has about 40% DoM and an average molecular weight of about 160 kDa is about 7:3; and wherein the composition comprises about 4.0% w/v of GelMA.
  • the polymer composition comprises: (a) about 2.0-3.0% w/v of GelMA, having about 40% DoM and an average molecular weight of about 90 kDa, and (b) about 0.5-1.5% w/v of GelMA, having about 40% DoM and an average molecular weight of about 160 kDa.
  • the polymer composition comprises: (a) about 2.5% w/v of GelMA, having about 40% DoM and an average molecular weight of about 90 kDa, and (b) about 1.0% w/v of GelMA, having about 40% DoM and an average molecular weight of about 160 kDa.
  • the polymer composition comprises: (a) 2.45% w/v of GelMA, having about 40% DoM and an average molecular weight of about 90 kDa, and (b) 1.05% w/v of GelMA, having about 40% DoM and an average molecular weight of about 160 kDa.
  • the polymer composition comprises: (a) about 2.0% w/v of GelMA, having about 40% DoM and an average molecular weight of about 90 kDa, and (b) about 1.0% w/v of GelMA, having about 40% DoM and an average molecular weight of about 160 kDa.
  • the polymer composition comprises: (a) 2.1% w/v of GelMA, having about 40% DoM and an average molecular weight of about 90 kDa, and (b) 0.9% w/v of GelMA, having about 40% DoM and an average molecular weight of about 160 kDa.
  • the GelMA is functionalized with at least one acrylate- PEG-arginine-glycine-aspartic acid-serine (acrylate-PEG -RGDS).
  • the polymer composition comprises about 5.0% w/v of GelMA, having about 60% DoM and an average molecular weight of about 90 kDa, and the GelMA is functionalized with at least one acrylate-PEG-arginine-glycine-aspartic acid-serine (acrylate-PEG -RGDS)
  • the chemically modified gelatin comprises gelatin acryloyl (GelAC).
  • At least one acrylated gelatin comprises gelatin glycidyl acrylate (GelGA).
  • the polymer composition comprises from about 0.5% to about 5.0% w/v of GelGA. In certain embodiments, the polymer composition from about 1% to about 3.5% w/v of GelGA. In certain embodiments, the polymer composition about 1.0% w/v of GelGA, about 2.5% w/v of GelGA, or about 3.5% w/v of GelGA.
  • the GelGA has a degree of functionalization (DoF) from about 45-60%. In certain embodiments, the GelGA has a degree of functionalization of about 45% or about 60% DoF. In certain embodiments, the GelGA in the polymer composition has an average molecular weight of about 7 kDa, about 11.5 kDa, more than 11.5 kDa, about 48 kDa, or about 50 kDa or more.
  • the GelGA in the polymer composition comprises: (i) about 70% of GelGA with an average molecular weight of about 7 kDa; (ii) about 20% of GelGA with an average molecular weight of about 48 kDa; (iii) about 10% of GelGA with an average molecular weight of about 50 kDa or more; or (iv) any combination of (i)-(iii).
  • the GelGA in the polymer composition comprises (i) about 70% of GelGA with an average molecular weight of about 7 kDa; (ii) about 20% of GelGA with an average molecular weight of about 48 kDa; and (iii) about 10% of GelGA with an average molecular weight of about 50 kDa or more.
  • the polymer composition comprises about 2.5% w/v of GelGA which has a DoF of about 45%, and (i) about 70% of GelGA with an average molecular weight of about 7 kDa; (ii) about 20% of GelGA with an average molecular weight of about 48 kDa; and (iii) about 10% of GelGA with an average molecular weight of about 50 kDa or more; optionally wherein the GelGA has about 45% DoF.
  • the polymer composition comprises about 1.0% w/v of GelGA which has a DoF of about 45%, and (i) about 70% of GelGA with an average molecular weight of about 7 kDa; (ii) about 20% of GelGA with an average molecular weight of about 48 kDa; and (iii) about 10% of GelGA with an average molecular weight of about 50 kDa or more; optionally wherein the GelGA has about 45% DoF.
  • the GelGA in the polymer composition comprises about 90% of GelGA with an average molecular weight of about 11.5 kDa and about 10% of GelGA with an average molecular weight of more than 11.5 kDa.
  • the polymer composition comprises about 2.5% w/v of GelGA which has a DoF of about 60%, and (i) about 90% of the Gel GA has an average molecular weight of about 11.5 kDa; and (ii) about 10% of the Gel GA has an average molecular weight of more than 11.5 kDa.
  • the polymer composition comprises about 3.5% w/v of Gel GA which has a DoF of about 60%, and (i) about 90% of the GelGA has an average molecular weight of about 11.5 kDa; and (ii) about 10% of the GelGA has an average molecular weight of more than 11.5 kDa.
  • the polymer composition comprises: (a) about 2.5% w/v of GelGA which has a DoF of about 60%, and (i) about 90% of the GelGA has an average molecular weight of about 11.5 kDa and (ii) about 10% of the GelGA has an average molecular weight of more than 11.5 kDa; and (b) about 2.0% w/v of GelMA, having about 10% DoM and an average molecular weight of about 160 kDa.
  • the polymer composition comprises polymer composition comprises: (a) about 1.0% w/v of GelGA which has a DoF of about 45%, and (i) about 70% of GelGA with an average molecular weight of about 7 kDa; (ii) about 20% of GelGA with an average molecular weight of about 48 kDa; and (iii) about 10% of GelGA with an average molecular weight of about 50 kDa or more; and (b) about 2.0% w/v of GelMA, having about 60% DoM and an average molecular weight of about 90 kDa.
  • the at least one acrylated gelatin comprises gelatin glycidyl methacrylate (GelGMA).
  • the polymer composition comprises about 10% w/v of GelGMA.
  • the GelGMA has a degree of functionalization (DoF) of about 30% DoF.
  • the GelGMA in the polymer composition has an average molecular weight of about 7 kDa, about 48 kDa, or about 50 kDa or more.
  • the GelGMA in the polymer composition comprises: (i) about 70% of GelGMA with an average molecular weight of about 7 kDa; (ii) about 20% of GelGMA with an average molecular weight of about 48 kDa; or (iii) about 10% of GelGMA with an average molecular weight of about 50 kDa or more.
  • the GelGMA in the polymer composition comprises (i) about 70% of GelGMA with an average molecular weight of about 7 kDa; (ii) about 20% of GelGMA with an average molecular weight of about 48 kDa; and (iii) about 10% of GelGMA with an average molecular weight of about 50 kDa or more.
  • the polymer composition comprises: about 10% w/v of GelGMA which has a DoF of about 30%, and (i) about 70% of GelGMA with an average molecular weight of about 7 kDa; (ii) about 20% of GelGMA with an average molecular weight of about 48 kDa; and (iii) about 10% of GelGMA with an average molecular weight of about 50 kDa or more; optionally wherein the GelGMA has about 45% DoF.
  • the population of cells comprise an endothelial cell.
  • the population of cells comprise a human umbilical vein endothelial cell (HUVEC).
  • the population of cells comprise an epithelial cell.
  • the population of cells comprise a human retinal pigment epithelium cell (HRPEC).
  • the population of cells comprise a human retinal pigment epithelium cell (HRPEC) derived from induced pluripotent stem cells (iPSC).
  • the population of cells comprise an ocular cell, or a pluripotent or embryonic stem cell derived ocular cell.
  • the polymer composition further comprises at least 0.1% (w/v) of a hydrophilic non-ionic surfactant.
  • the hydrophilic nonionic surfactant comprises at least one poloxamer surfactant such as Pol oxamer 407.
  • the composition comprises about 0.2% (w/v) of a poloxamer surfactant such as Poloxamer 407.
  • the present disclosure describes a precursor polymer composition, comprising a polymer composition of the present disclosure.
  • the present disclosure describes a gel polymer composition formed by photocrosslinking a precursor polymer composition of the present disclosure.
  • the present disclosure describes a hydrogel polymer composition formed by photocrosslinking a precursor polymer composition of the present disclosure.
  • the present disclosure provides a method for treating and/or repairing a defect, injury, and/or disease in a target soft tissue of a subject.
  • the present disclosure provides a method for treating and/or repairing a defect, injury, and/or disease in a target soft tissue of a subject, said method comprising: providing a precursor polymer composition of the present disclosure; administering the precursor polymer composition onto or under a surface of the target soft tissue of the subject, optionally the location of the soft tissue defect, injury, and/or disease; and crosslinking the precursor polymer composition by exposing the polymer crosslinking initiator in the polymer composition to crosslinking conditions, wherein the crosslinking of the precursor polymer composition produces a gel polymer composition.
  • the present disclosure provides a method for treating a defect, injury, and/or disease in a target soft tissue of a subject, said method comprising providing a gel polymer composition of the present disclosure and administering the gel polymer composition onto, under, or near a surface of the target soft tissue of the subject.
  • the gel polymer composition is administered at location of the soft tissue defect, injury, and/or disease.
  • the target soft tissue is ocular tissue.
  • the target soft tissue is subconjunctival ocular tissue or retinal ocular tissue.
  • the polymer composition is applied onto or under the surface of the ocular tissue by subconjunctival injection, subretinal injection, or suprachoroidal injection.
  • the defect, injury, and/or disease of the target soft tissue comprises an ocular defect, injury and/or disease; optionally an ocular ulcer such as a corneal ulcer from infections, injuries, perforations, or other defects.
  • the ocular defect, injury and/or disease comprises a retinal degeneration disease.
  • the ocular defect, injury and/or disease comprises age-related macular degeneration (AMD). In certain embodiments, the ocular defect, injury and/or disease comprises retinitis pigmentosa. In certain embodiments, the ocular defect, injury and/or disease comprises geographic atrophy.
  • AMD age-related macular degeneration
  • the ocular defect, injury and/or disease comprises retinitis pigmentosa. In certain embodiments, the ocular defect, injury and/or disease comprises geographic atrophy.
  • FIG. 1 provides an example of a reaction in which gelatin is modified with methacrylic anhydride (MA) to form a methacryloyl-substituted gelatin (GelMA).
  • MA methacrylic anhydride
  • FIG. 2 provides a method 100 for producing gel polymer compositions of the present disclosure.
  • FIG. 3 provides an example of a series of reactions to produce a GelMA hydrogel polymer composition from gelatin methacryloyl polymer precursors using a photoinitiator element and light energy.
  • FIG. 4A, FIG. 4B, FIG. 4C, FIG. 4D, FIG. 4E, and FIG. 4F present GFP+ cell imaging results for a transwell underside cell growth study using Human Umbilical Vein Endothelial Cells (HUVECs) and certain embodiments of hydrogel of the present disclosure.
  • FIG. 5A, FIG. 5B, and FIG. 5C present confocal imaging results for a transwell underside cell growth study using Human Umbilical Vein Endothelial Cells (HUVECs) and certain embodiments of hydrogel of the present disclosure.
  • FIG. 6F present GFP+ cell imaging results for a transwell underside cell growth study using Human Umbilical Vein Endothelial Cells (HUVECs) and certain embodiments of hydrogel of the present disclosure.
  • FIG. 7A, FIG. 7B, and FIG. 7C present Calcein AM+ based imaging results for a transwell underside cell growth study using Human Retinal Pigment Epithelium Cells (HRPEC) and certain embodiments of hydrogel of the present disclosure.
  • HRPEC Human Retinal Pigment Epithelium Cells
  • FIG. 8A, FIG. 8B, and FIG. 8C present Calcein AM+ based imaging results for a transwell topside cell growth study using Human Retinal Pigment Epithelium Cells (HRPEC) and certain embodiments of hydrogel of the present disclosure.
  • HRPEC Human Retinal Pigment Epithelium Cells
  • FIG. 9A provides live-cell Calcein AM imaging results related to in vitro retinal cell growth studies for hydrogel cell delivery formulations ( ⁇ 20 million cells/mL) of the present disclosure.
  • FIG. 9B provides measurement for fluid shear rates related to the extrusion of GelMA precursor polymer formulations through the small -diameter needle.
  • FIG. 9C provides live-cell Calcein AM imaging results related to in vitro retinal cell growth studies for hydrogel cell delivery formulations ( ⁇ 1 million cells/mL) of the present disclosure.
  • FIG. 9D provides live-cell imaging results (anti-CD73 and anti-rhodopsin) related to in vitro retinal cell growth studies for hydrogel cell delivery formulations of the present disclosure.
  • FIG. 10A provides study results for cell localization and migration studies for hydrogel formulations of the present disclosure.
  • FIG. 10B provides study results for hydrogel degradation studies for hydrogel formulations of the present disclosure.
  • FIG. 10C and FIG. 10D show images of retinal detachment related to hydrogel formulations of the present disclosure.
  • FIG. 10E is an image of human RPE cell deposition onto native pig RPE layers.
  • FIG. 11 provides cell growth study results related to hydrogel formulations of the present disclosure.
  • FIG. 12A and FIG. 12B present H&E and IHC cell count results for in vivo cell growth studies using Human Retinal Pigment Epithelium Cells (HRPEC) and certain embodiments of hydrogel of the present disclosure.
  • HRPEC Human Retinal Pigment Epithelium Cells
  • FIG. 13 presents the results of a cellular aggregation and viability studies using certain embodiments of hydrogel of the present disclosure.
  • FIG. 14 A, FIG. 14B, FIG. 14C, FIG. 14D, and FIG. 14E provide live-cell imaging results related to retinal cell growth studies for hydrogel cell delivery formulations of the present disclosure.
  • FIG. 15 shows imaging of cell flow through glass needle for PBS and G5(90/60) samples.
  • FIG. 16A, FIG. 16B, FIG. 16C, FIG. 16D, FIG. 16E, and FIG. 16F provide results comparing rabbit eyes after an injection of a formulation containing 1% GelMA (160/10) + 2.5% GelMA (90/60) + 375 k cell dose versus a suspension of cells or no cells following rapid retinal pigment epithelial (RPE) degeneration.
  • RPE retinal pigment epithelial
  • FIG. 17A, FIG. 17B, and FIG. 17C compares chemical and mechanical properties of various GelMA mixtures versus controls.
  • the present disclosure provides polymer compositions (e.g., acrylated gelatin polymer compositions) which have one or more advantages over compositions in current commercial use or known in the art.
  • the polymer compositions have one or more of the following advantages relative to one or more composition in current commercial use or known in the art: (i) lower in cost; (ii) easier to produce; (iii) improved biocompatibility; (iv) faster and/or stronger crosslinking and stabilization; (v) easier and/or more stable application; (vi) stronger adhesion and/or retention to target surface; (vii) degradation characteristics which can be engineered and adjusted; (viii) a smooth surface once applied; and/or (ix) higher cell viability or improved delivery for an encapsulated cell.
  • polymer compositions of the present disclosure facilitate stable and sustained delivery of one or more therapeutic agents or cells to a target tissue.
  • polymer compositions of the present disclosure facilitate controlled and sustained release of the one or more therapeutic agents or cells over a period of time to the target tissue.
  • polymer compositions of the present disclosure facilitate stable and sustained delivery and growth of cells at a target treatment site. As such, the polymer compositions of the present disclosure present clear improvements over compositions in current commercial use and currently known in the art.
  • polymer composition can refer to a precursor polymer composition (e.g., a polymer composition before crosslinking polymerization) and/or a gel polymer composition (e.g., a polymer composition after crosslinking polymerization), as provided by the corresponding context of the disclosure.
  • a precursor polymer composition e.g., a polymer composition before crosslinking polymerization
  • a gel polymer composition e.g., a polymer composition after crosslinking polymerization
  • examples of gel polymer compositions include hydrogels, and polymer compositions with increased viscosity (e.g., soft gels) resulting from crosslinking polymerization in the polymer composition.
  • a polymer component in the present disclosure can refer to a polymer precursor component (e.g., monomer or precursor oligomer), a crosslinked form of the polymer component in an oligomer (e.g., crosslinked oligomer), and/or a polymerized form of the polymer component in a gel polymer composition (e.g., hydrogel polymer), according to the context within the present disclosure.
  • a polymer precursor component e.g., monomer or precursor oligomer
  • a crosslinked form of the polymer component in an oligomer e.g., crosslinked oligomer
  • a polymerized form of the polymer component in a gel polymer composition e.g., hydrogel polymer
  • the polymer compositions comprise one or more chemically modified gelatins, such as gelatin methacryloyl (i.e., GelMA), gelatin acryloyl (GelAC), gelatin glycidyl acrylate (GelGA), gelatin glycidyl methacrylate (GelGMA), or combinations thereof.
  • the polymer compositions comprise gelatin methacryloyl (GelMA).
  • the polymer compositions comprise gelatin acryloyl (GelAC).
  • the polymer compositions comprise gelatin glycidyl acrylate (GelGA).
  • the polymer compositions comprise gelatin glycidyl methacrylate (GelGMA), or combinations thereof.
  • the polymer compositions comprise chemically modified gelatin (e.g., acrylated gelatin) and one or more crosslinking agents.
  • the polymer compositions comprise chemically modified gelatin (e.g., acrylated gelatin) and one or more polymer crosslinking initiators, such as light-activated photo-initiator elements.
  • the polymer compositions comprise chemically modified gelatin (e.g., acrylated gelatin), one or more crosslinking agents, and one or more polymer crosslinking initiators, such as light- activated photo-initiator elements.
  • the polymer compositions comprise acrylated gelatin, such as gelatin methacryloyl (i.e., GelMA), and a second acrylated gelatin, such as gelatin acryloyl (GelAC), gelatin glycidyl acrylate (GelGA).
  • the polymer compositions comprise a combination of GelMA and GelAC.
  • the polymer compositions comprise a combination of GelMA and GelGA.
  • the polymer compositions comprise a combination of GelMA and GelGMA.
  • the polymer compositions comprise a combination of GelAC and GelGA.
  • the polymer compositions comprise a combination of GelAC and GelGMA.
  • the polymer compositions comprise a combination of GelGA and GelGMA. [0078] In certain embodiments, the polymer compositions do not comprise a hydrolyzing enzyme. In certain embodiments, the polymer compositions do not comprise a glycosidase hydrolyzing enzyme.
  • the gel polymer composition is a hydrogel.
  • a hydrogel generally comprises a crosslinked polymeric framework which encompasses a network of pores filled with an interstitial solvent (e.g., a fluid) which includes water.
  • a hydrogel polymer composition has a water content of about 80% or more.
  • a hydrogel polymer composition has a water content of more than about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or more than about 99%.
  • a polymer composition e.g., hydrogel or hydrogel precursor
  • a polymer composition of the present disclosure e.g., acrylated gelatin polymer composition
  • a secondary hydrogelforming polymers component i.e., polymers or precursors thereof.
  • a polymer composition (e.g., hydrogel or hydrogel precursor) of the present disclosure is a primary polymer composition, and can include or be combined with one of more secondary hydrogel-forming polymers components selected from acrylamide, acrylic acid, alginate, alginate methacrylate, cellulose, chitosan, chitosan methacrylate, dimethacrylamide, methylenebisacrylamide, fibronectin, gelatin, gelatin methacrylate, glycol chitosan, glycol chitosan methacrylate, hexyl methacrylate, hyaluronic acid, hyaluronic acid methacrylate, hydroxyethyl methacrylate, hydroxyethyl acrylate, isopropyl acrylamide, isopropyl methacrylamide, laminin, methacrylamide, methacrylic acid, polyamide, polycaprolactone, polyethylene-gly
  • a secondary hydrogel polymer (formed from the secondary hydrogel-forming polymer precursors) is covalently crosslinked with the primary gel polymer composition (e.g., GelMA polymer composition).
  • the secondary hydrogel polymer (formed from the secondary hydrogel -forming polymer precursors) is not covalently crosslinked with the primary gel polymer composition (e.g., GelMA polymer composition), such, for example, the secondary hydrogel polymer forming a polymer network that is interwoven with the polymer network of the primary gel polymer composition.
  • a polymer composition of the present disclosure comprises one or more biocompatible polymer components or polysaccharides.
  • a polymer composition of the present disclosure comprises one or more biocompatible polymer components or polysaccharides selected from agarose, alginates, amylopectin, amylose, carrageenan, cellulose, chitin, chitosans, chondroitin sulfate, collagen, dermatan sulfate, dextran, elastin, elastin-like polypeptides (ELPs), tropoelastin, fibrin, fibrinogen, fibronectin, gelatin, glycogen, heparan, heparan sulfate, heparin, heparin sulfate, hyaluronans, hyaluronic acid, keratan sulfate, laminin, pectin, polyglycerol sebacate (PGS), polyethylene glycol (PEG), polylactic acid (PLA), polylysine, starch, thrombin, derivatives thereof, or a combination thereof.
  • PPS polyg
  • a polymer composition of the present disclosure comprises one or more cell-adhesion agents selected from fibronectin, laminin, vitronectin, RGD, vixapatin, derivatives thereof, or a combination thereof.
  • a polymer composition of the present disclosure comprises one or more synthetic polymer components, such as a biocompatible synthetic polymer component.
  • a polymer composition comprises one or more synthetic polymer components selected from polyurethanes, polysiloxanes, silicones, polyethylenes, polyvinyl pyrrolidones, polyhydroxy ethylmethacrylates (poly-HEMA), polymethyl methacrylates, polyvinyl alcohols, polyacrylic acids, polyacrylamides, polyethylene-co-vinyl acetates, polyethylene glycols, polymethacrylic acids, polylactic acids, polyglycolic acids, polylactide-co-glycolides, nylons, polyamides, polyanhydrides, polyethylene-co-vinyl alcohols, polycaprolactones, polyvinyl acetates, polyvinylhydroxides, polyethylene oxides, polyorthoesters, polyallyl amines, polyethylene imines, polyly
  • a polymer composition of the present disclosure comprises one or more polymer components (e.g., monomers, precursors, polymers) which include a crosslinkable group.
  • a polymer composition of the present disclosure comprises one or more polymer components which include a crosslinkable group selected from (or formed from reaction with) anhydrides, acid halides, carboxylic acids, diols, acrylic anhydrides, methacrylic anhydrides, acryloyl chlorides, acryloyl bromides, methacryloyl chlorides, methacryloyl bromides, acrylic acids, glycidyl methacrylates, methacrylic acids, dopamines, derivatives thereof, or combinations thereof.
  • HEMA hydroxy ethyl methacrylate
  • polymer composition can be present in a polymer composition at a concentration from about 1% and about 60% weight per volume (w/v).
  • a polymer composition of the present disclosure comprises one or more stabilizers and/or enhancers.
  • a polymer composition of the present disclosure comprises one or more stabilizers and/or enhancers selected from polar amino acids (e.g., tyrosine, cysteine, serine, threonine, asparagine, glutamine, aspartic acid, glutamic acid, arginine, lysine, and histidine), amino acid analogues, amino acid derivatives, collagen, divalent cation chelators (e.g., ethylenediaminetetraacetic acid (EDTA) or salts thereof), or a combination thereof.
  • polar amino acids e.g., tyrosine, cysteine, serine, threonine, asparagine, glutamine, aspartic acid, glutamic acid, arginine, lysine, and histidine
  • amino acid analogues e.g., amino acid derivatives, collagen, divalent cation
  • a polymer composition of the present disclosure can be clear and/or translucent. In certain embodiments, a polymer composition can be partially translucent or partially opaque. In certain embodiments, a polymer composition can be opaque.
  • the polymer compositions of the present disclosure can include the polymeric or therapeutic components, can be produced, can be analyzed or can be used as disclosed in US 20140377326, US 20150274805, US 20160175488, US 20170232138, US 20190022280 Al, WO 2020051133, and WO 2020081673, each of which is incorporated herein by reference in its entirety, insofar as each describes the composition, production, analysis and use of acrylated gelatin polymeric compositions such as GelMA hydrogels.
  • polymer compositions of the present disclosure comprises chemically-modified gelatin (e.g., acrylated gelatin such as GelMA).
  • chemically-modified gelatin e.g., acrylated gelatin such as GelMA.
  • polymer compositions of the present disclosure comprise combinations of precursor polymer components according from Table 1 (percentages are w/v concentration in the total precursor polymer formulation). Unless stated otherwise, GelMA materials in Table 1 are 160/80 (i.e., have 160 kDa molecular weight (MW) and 80% degree of methacrylation (DoM)).
  • polymer compositions of the present disclosure comprise combinations of precursor polymer components according from Table 2.
  • % w/v w/v concentration in the total precursor polymer formulation;
  • MW average molecular weight (kDa);
  • % DoF degree of functionalization (e.g., degree of methacrylation (DoM));
  • GAc* is acrylate-PEG-RGDS (arginine-glycine-aspartic acid-serine).
  • the polymer composition comprises GelMA having about 160 kDa molecular weight (MW). In certain embodiments, the polymer composition comprises GelMA having from about 80% to about 90% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having about 85% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having about 80% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having from about 75% to about 85% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having from about 70% to about 80% degree of methacryl ati on (DoM).
  • the polymer composition comprises GelMA having about 75% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having about 70% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having from about 65% to about 75% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having from about 60% to about 70% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having about 65% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having about 60% degree of methacrylation (DoM).
  • the polymer composition comprises GelMA having from about 55% to about 65% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having from about 50% to about 60% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having about 55% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having about 50% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having from about 45% to about 55% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having from about 40% to about 50% degree of methacrylation (DoM).
  • the polymer composition comprises GelMA having about 45% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having about 40% DoM. In certain embodiments, the polymer composition comprises GelMA having from about 35% to about 45% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having from about 30% to about 40% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having about 35% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having about 30% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having from about 25% to about 35% degree of methacrylation (DoM).
  • the polymer composition comprises GelMA having from about 20% to about 30% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having about 25% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having about 20% DoM. In certain embodiments, the polymer composition comprises GelMA having from about 15% to about 25% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having from about 10% to about 20% degree of methacrylation (DoM). In certain embodiments, the polymer composition comprises GelMA having about 15% DoM. In certain embodiments, the polymer composition comprises GelMA having about 10% DoM. In certain embodiments, the polymer composition comprises GelMA having about 5% DoM.
  • the polymer composition comprises GelMA having about 10% to about 40% DoM. In certain embodiments, the polymer composition comprises GelMA having about 50% to about 80% DoM. In certain embodiments, the polymer composition comprises GelMA having about 10 to about 20% DoM. In certain embodiments, the polymer composition comprises GelMA having about 7% DoM. In certain embodiments, the polymer composition comprises GelMA having about 5% DoM. In certain embodiments, the polymer composition comprises GelMA having about 5% to about 40% DoM. In certain embodiments, the polymer composition comprises GelMA having about 5% to about 20% DoM. In certain embodiments, the polymer composition comprises GelMA having about 1% to about 10% DoM.
  • the polymer composition comprises about 15% w/v of GelMA having an average molecular weight of about 160 kDa and a DoM of about 40%. In certain embodiments, the polymer composition comprises about 10% w/v of GelMA having an average molecular weight of about 138 kDa and a DoM of about 10%. In certain embodiments, the polymer composition comprises about 5% w/v of GelMA having an average molecular weight of about 160 kDa and a DoM of about 40%. In certain embodiments, the polymer composition comprises about 5% w/v of GelMA having an average molecular weight of about 160 kDa and a DoM of about 80%. In certain embodiments, the polymer composition comprises about 5% w/v of GelMA having an average molecular weight of about 138 kDa and a DoM of about 10%.
  • the polymer composition comprises about 2.5% w/v of GelMA having an average molecular weight of about 90 kDa and a DoM of about 60%. In certain embodiments, the polymer composition comprises about 5% w/v of GelMA having an average molecular weight of about 90 kDa and a DoM of about 60%. In certain embodiments, the polymer composition comprises about 1% w/v of GelMA having an average molecular weight of about 160 kDa and a DoM of about 10%. In certain embodiments, the polymer composition comprises about 2% w/v of GelMA having an average molecular weight of about 160 kDa and a DoM of about 10%. In certain embodiments, the polymer composition comprises about 2% w/v of GelMA having an average molecular weight of about 90 kDa and a DoM of about 60%.
  • the polymer composition comprises about 5% w/v of Gel AC.
  • the GelAC polymer is functionalized with 1.2% w/v acrylate-PEG-RGDS (arginine-glycine-aspartic acid-serine) having an average molecular weight of about 3.4 kDa.
  • the polymer composition comprises about 2.5% w/v of GelGA having a DoF (degree of functionalization) of about 45%, and a combination of molecular weights as follows: about 70% 7 kDA, about 20% 48 kDa, and about 10% greater than 50 kDa. In certain embodiments, the polymer composition comprises about 10% w/v of GelGA having a DoF (degree of functionalization) of about 30%, and a combination of molecular weights as follows: about 70% 7 kDA, about 20% 48 kDa, and about 10% greater than 50 kDa.
  • the polymer composition comprises about 1% w/v of GelGA having a DoF (degree of functionalization) of about 45%, and a combination of molecular weights as follows: about 70% 7 kDA, about 20% 48 kDa, and about 10% greater than 50 kDa. In certain embodiments, the polymer composition comprises about 2.5% w/v of GelGA having a DoF (degree of functionalization) of about 60%, and a combination of molecular weights as follows: about 90% 11.5 kDA and about 10% greater than 11.5 kDa.
  • the polymer composition comprises about 3.5% w/v of GelGA having a DoF (degree of functionalization) of about 60%, and a combination of molecular weights as follows: about 90% 11.5 kDA and about 10% greater than 11.5 kDa.
  • the polymer composition comprises a first acrylated gelatin and a second acrylated gelatin.
  • the polymer composition comprises: (a) about 2.5% w/v of GelMA having an average molecular weight of about 90 kDa and a DoM of about 60%; and (b) about 1% w/v of GelMA having an average molecular weight of about 160 kDa and a DoM of about 10%.
  • the polymer composition comprises: (a) about 1.0% w/v of GelMA having an average molecular weight of about 160 kDa and a DoM of about 40%; and (b) about 2.5% w/v of GelMA having an average molecular weight of about 90 kDa and a DoM of about 40%.
  • the polymer composition comprises: (a) 1.05% w/v of GelMA having an average molecular weight of about 160 kDa and a DoM of about 40%; and (b) 2.45% w/v of GelMA having an average molecular weight of about 90 kDa and a DoM of about 40%.
  • the polymer composition comprises: (a) about 1.0% w/v of GelMA having an average molecular weight of about 160 kDa and a DoM of about 40%; and (b) about 2.0% w/v of GelMA having an average molecular weight of about 90 kDa and a DoM of about 40%.
  • the polymer composition comprises: (a) 0.9% w/v of GelMA having an average molecular weight of about 160 kDa and a DoM of about 40%; and (b) 2.1% w/v of GelMA having an average molecular weight of about 90 kDa and a DoM of about 40%.
  • the polymer composition comprises: (a) about 2.5% w/v of GelGA having a DoF (degree of functionalization) of about 60%, and a combination of molecular weights as follows: about 90% 11.5 kDA and about 10% greater than 11.5 kDa; and (b) about 2% w/v of GelMA having an average molecular weight of about 160 kDa and a DoM of about 10%.
  • the polymer composition comprises: (a) about 1% w/v of GelGA having a DoF (degree of functionalization) of about 45%, and a combination of molecular weights as follows: about 70% 7 kDA, about 20% 48 kDa, and about 10% greater than 50 kDa; and (b) about 2% w/v of GelMA having an average molecular weight of about 90 kDa and a DoM of about 60%.
  • the polymer composition comprises: (a) about 5.0% w/v of GelMA having an average molecular weight of about 90 kDa and a DoM of about 60%; and (b) about 1.2% w/v of acrylate-PEG-RGDS (arginine-glycine-aspartic acid-serine) having an average molecular weight of about 3.4 kDa.
  • the polymer composition comprises a combination of a first GelMA mixture and a second GelMA mixture. In certain embodiments, the polymer composition comprises a combination of a first GelMA mixture and a second GelMA mixture, wherein the total GelMA in the polymer composition is from about 0.5% to about 5%. In certain embodiments, the polymer composition comprises a combination of a first GelMA mixture and a second GelMA mixture, wherein the total GelMA in the polymer composition is from about 2% to about 5%. In certain embodiments, the polymer composition comprises a combination of a first GelMA mixture and a second GelMA mixture, wherein the total GelMA in the polymer composition is from about 2% to about 4%.
  • the polymer composition comprises a combination of a first GelMA mixture and a second GelMA mixture, wherein the total GelMA in the polymer composition is from about 3% to about 5%. In certain embodiments, the polymer composition comprises a combination of a first GelMA mixture and a second GelMA mixture, wherein the total GelMA in the polymer composition is from about 3% to about 4%.
  • the polymer composition comprises from about 0.5% to about 3% of the first GelMA mixture. In certain embodiments, the polymer composition comprises from about 0.5% to about 3% of the second GelMA mixture. In certain embodiments, the polymer composition comprises from about 0.5% to about 3% of the first GelMA mixture, and about 0.5% to about 3% of the second GelMA mixture. In certain embodiments, the polymer composition comprises from about 0.5% to about 1.5% of the first GelMA mixture, and about 2% to about 3% of the second GelMA mixture. In certain embodiments, the polymer composition comprises from about 2% to about 3% of the first GelMA mixture, and about 0.5% to about 1.5% of the second GelMA mixture. In certain embodiments, the polymer composition comprises about 1% of the first GelMA mixture and about 2.5% of the second GelMA mixture.
  • the first GelMA mixture includes GelMA having a high average molecular weight (e.g., from 140 to 180 kDa, or about 160 kDa). In certain embodiments, the first GelMA mixture includes GelMA having a low degree of methacrylation (DOM) (e.g., from 5% to 40%, or about 10%). In certain embodiments, the first GelMA mixture includes GelMA having a high average molecular weight (e.g., from 140 to 180 kDa, or about 160 kDa) and a low DOM (e.g., from 5% to 40%, or about 10%).
  • DOM degree of methacrylation
  • the first GelMA mixture includes GelMA having an average molecular weight from 140 to 180 kDa and a DOM from 5% to 40%. In certain embodiments, the first GelMA mixture includes GelMA having an average molecular weight from 140 to 180 kDa and a DOM from 5% to 20%. In certain embodiments, the first GelMA mixture includes GelMA having an average molecular weight of about 160 kDa and a DOM of about 10%.
  • the second GelMA mixture includes GelMA having a low average molecular weight (e.g., from 75 to 115 kDa, or about 90 kDa). In certain embodiments, the second GelMA mixture includes GelMA having a high degree of methacrylation (DOM) (e.g., from 50% to 80%, or about 60%). In certain embodiments, the second GelMA mixture includes GelMA having a low average molecular weight (e.g., from 75 to 115 kDa, or about 90 kDa) and a high DOM (e.g., from 50% to 80%, or about 60%).
  • DOM degree of methacrylation
  • the second GelMA mixture includes GelMA having an average molecular weight from 75 to 115 kDa and a DOM from 50% to 80%. In certain embodiments, the second GelMA mixture includes GelMA having an average molecular weight from 80 to 115 kDa and a DOM from 50% to 70%. In certain embodiments, the second GelMA mixture includes GelMA having an average molecular weight of about 90 kDa and a DOM of about 60%.
  • the first GelMA mixture includes GelMA having a high average molecular weight (e.g., from 140 to 180 kDa, or about 160 kDa) and a low DOM (e.g., from 5% to 40%, or about 10%); and the second GelMA mixture includes GelMA having a low average molecular weight (e.g., from 75 to 115 kDa, or about 90 kDa) and a high DOM (e.g., from 50% to 80%, or about 60%).
  • a high average molecular weight e.g., from 140 to 180 kDa, or about 160 kDa
  • a low DOM e.g., from 5% to 40%, or about 10%
  • the second GelMA mixture includes GelMA having a low average molecular weight (e.g., from 75 to 115 kDa, or about 90 kDa) and a high DOM (e.g., from 50% to 80%, or about 60%).
  • the first GelMA mixture includes GelMA having an average molecular weight from 140 to 180 kDa and a DOM from 5% to 40%; and the second GelMA mixture includes GelMA having an average molecular weight from 75 to 115 kDa and a DOM from 50% to 80%.
  • the first GelMA mixture includes GelMA having an average molecular weight from 140 to 180 kDa and a DOM from 5% to 20%; and the second GelMA mixture includes GelMA having an average molecular weight from 80 to 100 kDa and a DOM from 50% to 70%.
  • the first GelMA mixture includes GelMA having an average molecular weight of about 160 kDa and a DOM of about 10%; and the second GelMA mixture includes GelMA having an average molecular weight of about 90 kDa and a DOM of about 60%.
  • the polymer composition comprises from about 0.5% to about 3% w/v of a first GelMA mixture, which includes GelMA having a high average molecular weight (e.g., from 140 to 180 kDa, or about 160 kDa) and a low DOM (e.g., from 5% to 40%, or about 10%).
  • the polymer composition comprises from about 0.5% to about 3% w/v of a second GelMA mixture, which includes GelMA having a low average molecular weight (e.g., from 75 to 115 kDa, or about 90 kDa) and a high DOM (e.g., from 50% to 80%, or about 60%).
  • the polymer composition comprises: from about 0.5% to about 3% w/v of a first GelMA mixture, which includes GelMA having a high average molecular weight (e.g., from 140 to 180 kDa, or about 160 kDa) and a low DOM (e.g., from 5% to 40%, or about 10%); and from about 0.5% to about 3% w/v of a second GelMA mixture, which includes GelMA having a low average molecular weight (e.g., from 75-115 kDa, or about 90 kDa) and a high DOM (e.g., from 50% to 80%, or about 60%).
  • a first GelMA mixture which includes GelMA having a high average molecular weight (e.g., from 140 to 180 kDa, or about 160 kDa) and a low DOM (e.g., from 5% to 40%, or about 10%)
  • a second GelMA mixture which includes GelMA having a low average molecular weight (e.g
  • the polymer composition comprises from about 0.5% to about 1.5% w/v of a first GelMA mixture, which includes GelMA having an average molecular weight from 140 to 180 kDa and a DOM from 5% to 40%; and from about 2% to about 3% w/v of a second GelMA mixture which includes GelMA having an average molecular weight from 75-115 kDa and a DOM from 50% to 80%.
  • the polymer composition comprises from about 0.5% to about 1.5% w/v of a first GelMA mixture, which includes GelMA having an average molecular weight from 140 to 180 kDa and a DOM from 5% to 20%; and from about 2% to about 3% w/v of a second GelMA mixture which includes GelMA having an average molecular weight from 85-100 kDa and a DOM from 50% to 70%.
  • the polymer composition comprises about 1% w/v of a first GelMA mixture which includes GelMA having an average molecular weight of about 160 kDa and a DOM of about 10%; and about 2.5% w/v of a second GelMA mixture which includes GelMA having an average molecular weight of about 90 kDa and a DOM of about 60%.
  • the polymer composition comprises a combination of GelMA having about 10% DoM (e.g., GelMA 160/10) and GelMA having about 80% DoM (e.g., GelMA 160/80). In certain embodiments, the polymer composition comprises a combination of GelMA having about 10% DoM and GelMA having about 80% DoM, wherein the polymer composition comprises about 4 to 10% w/v of GelMA. In certain embodiments, the polymer composition comprises a combination of GelMA having about 10% DoM (e.g., GelMA 160/10) and GelMA having about 80% DoM (e.g., GelMA 160/80), wherein the ratio of 10% DoM GelMA and 80% DoM GelMA is from about 1 :9 to about 9: 1.
  • the ratio of 10% DoM GelMA and 80% DoM GelMA is about 1:9. In certain embodiments, the ratio of 10% DoM GelMA and 80% DoM GelMA is about 2:8 (i.e., about 1:4). In certain embodiments, the ratio of 10% DoM GelMA and 80% DoM GelMA is about 3:7. In certain embodiments, the ratio of 10% DoM GelMA and 80% DoM GelMA is about 4:6 (i.e., about 2:3). In certain embodiments, the ratio of 10% DoM GelMA and 80% DoM GelMA is about 5:5 (i.e., about 1:1).
  • the ratio of 10% DoM GelMA and 80% DoM GelMA is about 4:6 (i.e., about 2:3). In certain embodiments, the ratio of 10% DoM GelMA and 80% DoM GelMA is about 3:7. In certain embodiments, the ratio of 10% DoM GelMA and 80% DoM GelMA is about 2:8 (i.e., about 1 :4). In certain embodiments, the ratio of 10% DoM GelMA and 80% DoM GelMA is about 1 :9.
  • the polymer composition comprises glycidyl methacrylate-functionalized gelatin having about 45% DoM (e.g., GelGA 160/45). In certain embodiments, the polymer composition comprises glycidyl methacrylate-functionalized gelatin having about 45% DoM and 160 kDa (GelGA 160/45). In certain embodiments, the polymer composition comprises glycidyl methacrylate-functionalized gelatin having about 45% DoM and 90 kDa (GelGA 90/45).
  • DoM e.g., GelGA 160/45
  • the polymer composition comprises glycidyl methacrylate-functionalized gelatin having about 45% DoM and 160 kDa (GelGA 90/45).
  • the polymer composition comprises a poloxamer surfactant (e.g., Poloxamer 407). In certain embodiments, the polymer composition comprises about 0.1-0.5% w/v (e.g., about 0.2% w/v) of a poloxamer surfactant (e.g., Poloxamer 407). In certain embodiments, the polymer composition comprises a tyloxapol surfactant. In certain embodiments, the polymer composition comprises about 0.1-0.5% w/v (e.g., about 0.1% w/v) of a tyloxapol surfactant.
  • a poloxamer surfactant e.g., Poloxamer 407
  • the polymer composition comprises about 0.1-0.5% w/v (e.g., about 0.2% w/v) of a poloxamer surfactant (e.g., Poloxamer 407).
  • the polymer composition comprises a tyloxapol surfactant.
  • the polymer composition comprises about
  • the polymer composition comprises about 2% GelMA (10-40% DoM). In certain embodiments, the polymer composition comprises about 4% Gelatin Acrylate (10-40% DoM). In certain embodiments, the polymer composition comprises about 2% Gelatin Acrylate (10-40% DoM). In certain embodiments, the polymer composition comprises about 5-20% GelMA (10-40% DoM).
  • the polymer composition comprises about 4% GelMA (80% DoM) and about 0.2% (w/v) of a poloxamer surfactant (e.g., Poloxamer 407); optionally with a therapeutic agent (e.g., corticosteroid) or a cell.
  • a poloxamer surfactant e.g., Poloxamer 407
  • a therapeutic agent e.g., corticosteroid
  • the polymer composition comprises about 4% GelMA (40% DoM) and about 0.2% (w/v) of a poloxamer surfactant (e.g., Poloxamer 407); optionally with a therapeutic agent (e.g., corticosteroid) or a cell.
  • the polymer composition comprises about 4% GelMA (10% DoM) and about 0.2% (w/v) of a poloxamer surfactant (e.g., Poloxamer 407); optionally with a therapeutic agent (e.g., corticosteroid) or a cell.
  • a poloxamer surfactant e.g., Poloxamer 407
  • a therapeutic agent e.g., corticosteroid
  • the polymer composition comprises about 20% GelMA (40% DoM); and about 0.2% (w/v) of a poloxamer surfactant (e.g., Poloxamer 407); optionally with a therapeutic agent (e.g., corticosteroid) or a cell.
  • Gelatin is a naturally derived, biocompatible mixture of peptides and proteins derived from collagen, which is a primary structural component of animal tissue (including ocular tissue, bones, and skin).
  • Natural matrix peptides and proteins e.g., denatured collagen
  • gelatin materials can include gelatin components derived from animals including, but not limited to, pig, cow, horse, chicken, and fish.
  • gelatin materials can be derived from connective tissue proteins, such as collagen.
  • gelatin materials can be derived from bone, skin, or ocular tissues.
  • gelatin materials can be prepared by acid hydrolysis and/or base hydrolysis of connective tissue proteins (e.g., collagen).
  • polymer compositions of the present disclosure comprise a chemically modified gelatin.
  • the polymer compositions comprise acrylated gelatin.
  • the polymer compositions comprise gelatin methacryloyl (i.e., GelMA).
  • the polymer compositions comprise gelatin acryloyl (i.e., GelAC).
  • the polymer compositions comprise gelatin glycidyl acrylate (i.e., GelGA).
  • the polymer compositions comprise gelatin glycidyl methacrylate (i.e., GelGMA).
  • a chemically modified gelatin can be included in precursor polymer compositions of the present disclosure.
  • the chemically modified gelatin comprises a photo-crosslinkable derivative of gelatin.
  • the chemically modified gelatin can be modified with an acrylic anhydride or acryloyl chloride (substituted or unsubstituted) to form an acryloyl-substituted gelatin.
  • the chemically modified gelatin can be modified with one or more crosslinkable groups selected from methyl acrylate, ethyl acrylate, propyl acrylate, methyl methacrylate, ethyl methacrylate, methacryloyl, catechol, ethylene oxide, or propylene oxide.
  • the chemically modified gelatin can be modified with methacrylic anhydride (MA) (also known as methacryloyl anhydride) to form a methacryloyl-substituted gelatin (commonly referred to as gelatin methacryloyl, or GelMA).
  • MA methacrylic anhydride
  • FIG. 1 provides an example of a reaction in which gelatin is modified with methacrylic anhydride to form a methacryloyl-substituted gelatin (GelMA).
  • acryloyl modification of gelatin can be performed by a synthesis reaction of gelatin with a functionalizing compound which comprises an acrylate group.
  • methacryloyl modification of gelatin can be performed by a synthesis reaction of gelatin with methacrylic anhydride, methacryloyl chloride, 2- isocyanatoethyl methacrylate, 2-hydroxyethyl methacrylate, glycidyl methacrylate, methacrylic acid N-hydroxysuccinimide ester, allyl methacrylate, vinyl methacrylate, bis(2- methacryloyl)oxyethyl disulfide, 2-hydroxy-5-N-methacrylamidobenzoic acid, or combinations thereof.
  • acryloyl-substituted gelatin and “acrylated gelatin” can describe a gelatin having free amines (e.g., lysine, arginine, asparagine, or glutamine side chains) and/or free hydroxyls (e.g., serine, threonine, aspartic acid or glutamic acid side chains) that have been substituted with at least one acryloyl group, such as acrylamide, methacrylamide, hydroxyethyl acrylate (i.e., glycidyl acrylate), or hydroxyethyl methacrylate (i.e., glycidyl methacrylate).
  • free amines e.g., lysine, arginine, asparagine, or glutamine side chains
  • free hydroxyls e.g., serine, threonine, aspartic acid or glutamic acid side chains
  • the R group includes a terminal amine and/or hydroxyl group on the gelatin which is subject to the acryloyl functional
  • the R’ group of the acryloyl moiety is methyl, commonly referred to as a methacryloyl group.
  • methacryloyl-substituted gelatin can describe a gelatin having free amines (e.g., lysine, arginine, asparagine, or glutamine side chains) and/or free hydroxyls (e.g., serine, threonine, aspartic acid or glutamic acid side chains) that have been substituted with at least one methacryloyl group, such as methacrylamide groups (from free amines on the gelatin) and/or a methacrylate groups (from free hydroxyls on the gelatin).
  • gelatin acryloyl can describe a gelatin having free amines (e.g., lysine, arginine, asparagine, or glutamine side chains) and/or free hydroxyls (e.g., serine, threonine, aspartic acid or glutamic acid side chains) that have been substituted with at least one methacryloyl group, such as methacrylamide groups (from free amines on the gelatin) and/or a methacrylate groups (from free hydroxyls on the gelatin).
  • methacryloyl group such as methacrylamide groups (from free amines on the gelatin) and/or a methacrylate groups (from free hydroxyls on the gelatin).
  • the terms “gelatin glycidyl acrylate” and “GelGA” can describe an acrylated gelatin having free amines (e.g., lysine, arginine, asparagine, or glutamine side chains) and/or free hydroxyls (e.g., serine, threonine, aspartic acid or glutamic acid side chains) that have been substituted with at least one hydroxyethyl acryloyl group, such as a hydroxyethyl acrylate group (i.e., glycidyl acrylate group).
  • free amines e.g., lysine, arginine, asparagine, or glutamine side chains
  • free hydroxyls e.g., serine, threonine, aspartic acid or glutamic acid side chains
  • the terms “gelatin glycidyl methacrylate” and “GelGMA” can describe an acrylated gelatin having free amines (e.g., lysine, arginine, asparagine, or glutamine side chains) and/or free hydroxyls (e.g., serine, threonine, aspartic acid or glutamic acid side chains) that have been substituted with at least one hydroxy ethyl methacryloyl group, such as a hydroxyethyl methacrylate group (i.e., glycidyl methacrylate group).
  • free amines e.g., lysine, arginine, asparagine, or glutamine side chains
  • free hydroxyls e.g., serine, threonine, aspartic acid or glutamic acid side chains
  • a chemically modified gelatin e.g., acrylated gelatin
  • a chemically-modified gelatin e.g., acrylated gelatin
  • a weight per volume concentration w/v
  • a chemically-modified gelatin e.g., acrylated gelatin
  • a weight per volume concentration of from about 1-3%, about 3-6%, about 6-10%, about 1-5%, about 1-10%, about 5-10%, about 11-13%, about 13-16%, about 16-20%, about 10-20%, about 10-15%, about 15-20%, about 21-23%, about 23-26%, about 26-30%, about 20-30%, about 20-25%, about 25-30%, about 31-33%, about 33-36%, about 36-40%, about 30-40%, about 30-35%, about 35-40%, about 41-43%, about 43-46%, about 46-50%, about 40-50%, about 40-45%, about 45-50%, about 51-53%, about 53-56%, about 56-60%, about 50-60%, about 50-55%, or about 55-60%.
  • w/v weight per volume concentration
  • a polymer composition comprises acrylated gelatin (i.e., GelMA) with a degree of acryloyl substitution (i.e., methacryloyl functionalization).
  • degree of acryloyl substitution and “degree of functionalization” (DoF) can describe the percentage of free amines and hydroxyls in a gelatin that have been substituted with acryloyl groups (i.e., functionalized).
  • degree of methacryloyl substitution DoM
  • DoM degree of methacryloyl substitution
  • a polymer composition comprises acrylated gelatin with a degree of acryloyl substitution of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%.
  • a polymer composition comprises acrylated gelatin with a degree of acryloyl substitution from about 10-99%.
  • the degree of acryloyl substitution is from about 1- 5%, about 5-10%, about 10-15%, about 15-20%, about 20-25%, about 25-30%, about 30- 35%, about 35-40%, about 40-45%, about 45-50%, about 50-55%, about 55-60%, about 60- 65%, about 65-70%, about 70-75%, about 75-80%, about 80-85%, about 85-90%, about 90- 95%, or about 95-99%.
  • a polymer compositions comprises GelMA with a degree of methacryloyl substitution of from about 1-5%, about 5-10%, about 10-15%, about 15-20%, about 20-25%, about 25-30%, about 30-35%, about 35-40%, about 40-45%, about 45-50%, about 50-55%, about 55-60%, about 60-65%, about 65-70%, about 70-75%, about 75-80%, about 80-85%, about 85-90%, about 90-95%, or about 95-99%.
  • a polymer composition comprises GelMA with a degree of methacrylamide substitution (i.e., methacrylamide functionalization).
  • a polymer composition comprises GelMA with a degree of methacrylamide substitution of at least about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or at least about 90%.
  • a polymer composition comprises GelMA with a degree of methacrylamide substitution from about 20-90%.
  • the degree of methacrylamide substitution is from about 1-5%, about 5-10%, about 10-15%, about 15-20%, about 20-25%, about 25-30%, about 30-35%, about 35-40%, about 40-45%, about 45-50%, about 50-55%, about 55-60%, about 60-65%, about 65-70%, about 70-75%, about 75-80%, about 80-85%, or about 85-90%.
  • the degree of methacrylamide substitution can be measured using proton nuclear magnetic resonance.
  • the degree of methacrylamide substitution can be measured using a fluoraldehyde assay.
  • a polymer composition comprises GelMA with a degree of methacrylate substitution (i.e., methacrylate functionalization).
  • a polymer composition comprises GelMA with a degree of methacrylate substitution of at least about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or at least about 90%.
  • a polymer composition comprises GelMA with a degree of methacrylate substitution from about 20-90%.
  • the degree of methacrylate substitution is from about 1-5%, about 5-10%, about 10-15%, about 15-20%, about 20-25%, about 25-30%, about 30-35%, about 35-40%, about 40-45%, about 45-50%, about 50-55%, about 55-60%, about 60-65%, about 65-70%, about 70-75%, about 75-80%, about 80-85%, or about 85-90%.
  • the degree of methacrylate substitution can be measured using proton nuclear magnetic resonance.
  • the degree of methacrylate substitution can be measured using a Fe(III)- hydroxamic acid-based assay.
  • measurement of the degree of methacrylate substitution can include an aminolysis reaction (e.g., by exposure to a hydroxylamine solution) to convert methacrylate groups into N-hydroxymethacrylamide groups.
  • a polymer composition comprises GelMA with a degree of methacrylamide substitution and with a degree of methacrylate substitution.
  • the ratio of methacrylamide substitution to methacrylate substitution in the GelMA is from about 1:1 to 99:1.
  • the ratio of methacrylamide substitution to methacrylate substitution is from about 1:1 to 2: 1, about 2:1 to 3 : 1, about 3 : 1 to 4:1, about 4:1 to 5:1, about 1:1 to 5:1, about 5:1 to 10:1, about 10:1 to 15:1, about 15:1 to 20:1, about 20:1 to 25:1, about 25:1 to 30:1, about 30:1 to 35:1, about 35:1 to 40:1, about 40:1 to 45:1, about 45:1 to 50:1, about 50:1 to 55:1, about 55:1 to 60:1, about 60:1 to 65:1, about 65:1 to 70:1, about 70:1 to 75:1, about 75:1 to 80:1, about 80:1 to 85:1, about 85:1 to 90:1, about 90:1 to 95:1, or about 95:1 to 99:1.
  • the ratio of methacrylate substitution to methacrylamide substitution in the GelMA is from about 1:1 to 99:1. In some embodiments, the ratio of methacrylate substitution to methacrylamide substitution is from about 1:1 to 2:1, about 2:1 to 3:1, about 3:1 to 4:1, about 4:1 to 5:1, about 1:1 to 5:1, about 5:1 to 10:1, about 10:1 to 15:1, about 15:1 to 20:1, about 20:1 to 25:1, about 25:1 to 30:1, about 30:1 to 35:1, about 35:1 to 40:1, about 40:1 to 45:1, about 45:1 to 50:1, about 50:1 to 55:1, about 55:1 to 60:1, about 60:1 to 65:1, about 65:1 to 70:1, about 70:1 to 75:1, about 75:1 to 80:1, about 80:1 to 85:1, about 85:1 to 90:1, about 90:1 to 95:1, or about 95:1 to 99:1.
  • the polymer composition comprises GelMA with a methacryloyl modification of gelatin performed by a reaction of gelatin with methacrylic anhydride. In certain embodiments, the polymer composition comprises GelMA with a methacryloyl modification of gelatin performed by a reaction of gelatin with glycidyl methacrylate.
  • a gelatin can be functionalized with anchoring integrins and/or proteins (e.g., proteins which bind to the surface proteins of a target surface). Said functionalization can occur with polymeric linkers between the gelatin and integrin and/or protein.
  • a polymer composition of the present disclosure comprises a crosslinking agent.
  • crosslinking agent can describe a substance which forms, promotes, or regulates intermolecular bonding (covalent, ionic, hydrogen) between polymeric units or chains to create a network of polymeric chains.
  • Crosslinking agents typically exhibit one or more, optionally two or more, bonding functionalities which can create chemical bonds between two or more polymer chains.
  • Crosslinking agents can include, for example, two vinyl bonds (tetrafunctionality), or three amines (trifunctionality).
  • a polymer composition comprises a crosslinking agent which can be used to activate or facilitate polymerization, gelation, and solidification of the polymer composition from a precursor polymer composition to a gel polymer composition.
  • a polymer composition of the present disclosure e.g., precursor polymer composition
  • crosslinking conditions e.g.
  • acryloyl groups in the polymer composition e.g., acryloyl-substituted gelatin and other acryloyl-based crosslinking agents
  • acryloyl groups in the polymer composition e.g., acryloyl-substituted gelatin and other acryloyl-based crosslinking agents
  • other acryloyl groups to crosslink the polymer composition e.g., acrylated gelatin hydrogel
  • a polymer composition of the present disclosure comprises from about 1% and about 50% (w/v) of one or more crosslinking agents.
  • the polymer composition comprises one or more crosslinking agents at a concentration (w/v) of at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%.
  • the polymer composition comprises one or more crosslinking agents at a concentration (w/v) of no more than about 50%, about 45%, about 40%, about 35%, or about 30%.
  • the polymer composition comprises one or more crosslinking agents at a concentration (w/v) of from about 1-3%, about 3-6%, about 6-10%, about 1-5%, about 1- 10%, about 5-10%, about 11-13%, about 13-16%, about 16-20%, about 10-20%, about 10- 15%, about 15-20%, about 21-23%, about 23-26%, about 26-30%, about 20-30%, about 20-
  • a polymer composition of the present disclosure comprises one or more crosslinking agents selected from glutaraldehyde, epoxides (e.g., bisoxiranes), oxidized dextran, p-azidobenzoyl hydrazide, N-(a-maleimidoacetoxy)succinimide ester, p-azidophenyl glyoxal monohydrate, bis-((4-azidosalicylamido)ethyl)disulfide, bis(sulfosuccinimidyl)suberate, dithiobis(succinimidyl proprionate), disuccinimidyl suberate, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), ethoxylated trimethylpropane triacrylate, N-hydroxysuccinimide (NHS), derivatives thereof,
  • crosslinking agents selected from
  • a polymer composition of the present disclosure comprises one or more crosslinking agents selected from polyethyleneoxide dimethacrylate, methylene bisacrylamide, methylene bis(2 -methylacrylamide), methylene diacrylate, methylene bis(2 -methylacrylate), diethylene glycol diacrylate, hexamethylene diacrylate, hexamethylene diisocyanate, oxybis(methylene) bis(2 -methylacrylate), oxybis(ethane-2,l- diyl) bis(2 -methylacrylate), trimethylolpropane triacrylate, pentaerythritol triacrylate, tris (2- hydroxy ethyl) isocyanurate triacrylate, isocyanuric acid tris(2 -acryloyloxyethyl) ester, ethoxylated trimethylolpropane triacrylate, pentaerythrityl triacrylate and glycerol triacrylate, phosphin
  • a polymer composition comprises one or more photoinitiator elements (i.e., a crosslinking initiator which is initiated or activated by absorbing a certain wavelength of light).
  • precursor polymer compositions of the present disclosure comprise one or more photo-initiator elements.
  • the photo-initiator element can be activated by exposure to light.
  • light exposure can activate the photo-initiator to form free-radicals, wherein the free radicals can result in bond formation between reactive groups in the composition, such as vinyl-bond crosslinking between methacrylate groups in a GelMA polymer composition.
  • a photo-initiator element can be activated by exposure to one or more light sources selected from visible light sources (e.g., white or blue light), ultraviolet (UV) light sources, near-infrared (NIR) light sources, and fluorescent light sources.
  • the photo-initiator element comprises a visible light- activated photo-initiator, such as a visible light-activated photo-initiator which is activated upon exposure to light having a wavelength from about 380 nm to about 740 nm.
  • the visible light-activated photo-initiator can be activated upon exposure to light having a wavelength of from about 380-435 nm (i.e.
  • the photo-initiator element comprises an ultraviolet light-activated photo-initiator.
  • the photo-initiator element comprises a near-infrared (NIR) light-activated photo-initiator.
  • the photo-initiator element comprises a white light- activated photo-initiator.
  • the photo-initiator element comprises a blue light-activated photo-initiator.
  • a polymer composition comprises one or more photoinitiator elements selected from: methylene bisacrylamide (MBA), triethanolamine; 1-Vinyl- 2-pyrrolidone (NVP); N-vinylcaprolactam (NVC); Ethylene Glycol Diacrylate (EGDA); riboflavin; azobisisobutyronitrile; benzoyl peroxide; 1 -benzoylcyclohexanol; di -tert-butyl peroxide; Eosin Y (e.g., disodium salt), (2-(2,4,5,7-tetrabromo-6-oxido-3-oxo-3H-xanthen-9- yl) benzoate); 4,6-trimethylbenzoylphosphinate; triethanol amine; 2, 3 -diketo- 1,7,7- trimethylnorcamphane; 1 -phenyl- 1,2-propadi one; 2,4,6- trimethylbenzo
  • the polymer crosslinking initiator comprises eosin Y or eosin Y disodium salt (EYDS). In certain embodiments, a polymer crosslinking initiator comprises methylene bisacrylamide (MBA). In certain embodiments, the polymer crosslinking initiator comprises triethanolamine. In certain embodiments, a polymer composition comprises a combination of Eosin Y, triethanolamine, and/or vinyl caprolactam. In certain embodiments, the polymer crosslinking initiator comprises eosin Y disodium salt (EYDS), N-vinyl caprolactam (NVC), triethanolamine, or any combination thereof.
  • EYDS eosin Y disodium salt
  • NVC N-vinyl caprolactam
  • the polymer crosslinking initiator comprises eosin Y disodium salt (EYDS), N-Vinylpyrrolidone (NVP), triethanolamine, or any combination thereof.
  • the polymer crosslinking initiator comprises eosin Y disodium salt (EYDS), methylene bisacrylamide (MBA), triethanolamine, or any combination thereof.
  • the polymer crosslinking initiator comprises: (i) about 50 pM eosin Y or eosin Y disodium salt (EYDS), optionally about 50 pM eosin Y disodium salt (EYDS); (ii) from about 1.0 to about 5.0 pL/mL of N-vinyl caprolactam (NVC) or N- Vinylpyrrolidone (NVP), optionally from about 3.5 to about 5.0 pL/mL of NVP, optionally about 5.0 pL/mL of NVP; and (iii) triethanolamine, optionally about 1.5% v/v of triethanolamine.
  • EYDS eosin Y or eosin Y disodium salt
  • EYDS eosin Y disodium salt
  • NVC N-vinyl caprolactam
  • NVP N- Vinylpyrrolidone
  • triethanolamine optionally about 1.5% v/v of triethanolamine.
  • the polymer crosslinking initiator comprises from about 0.2-0.3% methylene bisacrylamide (MBA). In certain embodiments, the polymer crosslinking initiator comprises about 0.25 methylene bisacrylamide (MBA).
  • the polymer crosslinking initiator comprises: (i) from about 40-60 pM eosin Y disodium salt (EYDS); (ii) from about 0.2-0.3% methylene bisacrylamide (MBA); and (iii) about 1.0-2.0% v/v of triethanolamine. In certain embodiments, the polymer crosslinking initiator comprises: (i) about 50 pM eosin Y disodium salt (EYDS); (ii) about 0.25% methylene bisacrylamide (MBA); and (iii) about 1.5% v/v of triethanolamine.
  • a polymer composition comprises one or more photoinitiator elements selected from: acetophenone; anisoin; anthraquinone; anthraquinone-2- sulfonic acid, sodium salt monohydrate; (benzene) tricarbonylchromium; 4-(boc- aminomethyl)phenyl isothiocyanate; benzin; benzoin; benzoin ethyl ether; benzoin isobutyl ether; benzoin methyl ether; benzoic acid; benzophenyl-hydroxycyclohexyl phenyl ketone; 3, 3’, 4, 4’- benzophenone tetracarboxylic dianhydride; 4-benzoylbiphenyl; 2-benzyl-2- (dimethylamino)-4’- morpholino butyrophenone; 4,4’-bis(diethylamino)benzophenone; 4,4’- bis(dimethylamino)
  • 2,4,6,- trimethylbenzoyldiphenyl phosphine oxide 2,4,6-trimethyl benzophenone; blend of 4- methylbenzophenone and benzophenone; oligo(2-hydroxy-2-methyl-l-(4(l- methylvinyl)phenyl)propanone; oligo(2-hydroxy-2-methyl-l-4(l-methylvinyl)phenyl propanone and 2-hydroxy-2-methyl-l-phenyl-l-propanone; 4-methylbenzophenone; trimethylbenzophenone and methylbenzophenone; and water emulsion of 2,4,6- trimethylbenzoylphosphine oxide, alpha hydroxyketone, trimethylbenzophenone, and 4- methyl benzophenone.
  • a polymer composition comprises one or more cationic and/or anionic photo-initiator elements selected from: titanium tetrachloride, vanadium tetrachloride, bis(cyclopentadienyl)titanium dichloride, ferrocene, cyclopentadienyl manganese tricarbonyl, manganese decacarbonyl, diazonium salts, diaryliodonium salts (e.g., 3,3’-dinitrodiphenyliodonium hexafluoroarsenate, diphenyliodonium fluoroborate, 4- methoxydiphenyliodonium fluoroborate) and triarylsulfonium salts.
  • cationic and/or anionic photo-initiator elements selected from: titanium tetrachloride, vanadium tetrachloride, bis(cyclopentadienyl)titanium dichloride, ferrocene, cycl
  • a polymer composition comprises a crosslinking agent or initiator which comprises one or more metal 2+ ions and/or metal 3+ ions.
  • a polymer composition comprises a crosslinking agent which comprises one or more metal 2+ ions and/or metal 3+ ions selected from Fe 2+ , Fe 3+ , Ni 2+ , Zn 2+ , Cu 2+ , Ag 2+ , Au 3+ , Co 2+ , Co 3+ , Cr 2 , Cr 3+ , Cd 2+ , Mn 2+ , Mg 2+ , Pd 2+ , Pt 2+ , Al 3+ , or combinations thereof.
  • a precursor polymer composition of the present disclosure comprises both one or more photoinitiators element and one or more metal 2+/3+ ions.
  • a polymer composition comprises a crosslinking agent or initiator which uses Click bioconjugation chemistry for polymeric crosslinking.
  • the polymer composition comprises a crosslinking agent or initiator which uses Click bioconjugation chemistry selected from metal -catalyzed azide-alkyne cycloaddition, strain-promoted azide-alkyne cycloaddition, strain-promoted alkyne-nitrone cycloaddition (e.g., Alkene/azide [3+2] cycloaddition, Alkene/tetrazine inverse-demand Diels-Alder, Alkene/tetrazole photoclick reaction), or a combination thereof.
  • Click bioconjugation chemistry selected from metal -catalyzed azide-alkyne cycloaddition, strain-promoted azide-alkyne cycloaddition, strain-promoted alkyne-nitron
  • the viscosity of a material is a measurement of the resistance of the material to deformation at a given rate.
  • the viscosity of a fluid material is often correlated with the thickness and/or density of that material.
  • polymer compositions of the present disclosure can have a therapeutically effective viscosity.
  • a polymer composition can have a viscosity which provides for strong adhesion and high retention of the polymer composition on a target tissue of a subject.
  • a precursor polymer composition of the present disclosure can have a viscosity which provides for strong adhesion and high retention of the polymer composition on a target tissue of a subj ect.
  • a precursor polymer composition can have a viscosity which is greater than water.
  • a precursor polymer composition can have a viscosity which is equivalent to a paste.
  • a gel polymer composition of the present disclosure can have a viscosity which provides for strong adhesion and high retention of the polymer composition on a target tissue of a subject.
  • a precursor polymer composition can have a viscosity which is equivalent to water.
  • a gel polymer composition can retain its shape and/or consistency on the surface of a target tissue for one or more hours, one or more days, or one or more weeks.
  • a polymer composition can have a viscosity from about 0.5 Pascal-seconds (Pa s) to about 300 Pa s at a low shear rate (e.g., at a shear rate of about 0.001 s' 1 to about 1 s' 1 ). In certain embodiments, the polymer composition can have a viscosity from about 0.5-100 Pa s at a low shear rate.
  • the polymer composition can have a viscosity, at a low shear rate, of from about 0.5-5 Pa s, about 5-10 Pa s, about 10-15 Pa s, about 15-20 Pa s, about 20-25 Pa s, about 25-30 Pa s, about 30-35 Pa s, about 35-40 Pa s, about 40-45 Pa s, about 45-50 Pa s, about 50-55 Pa s, about 55-60 Pa s, about 60-65 Pa s, about 65-70 Pa s, about 70-75 Pa s, about 75-80 Pa s, about 80-85 Pa s, about 85-90 Pa s, about 90-95 Pa s, about 95-100 Pa s, about 100-125 Pa s, about 125- 150 Pa s, about 150-175 Pa s, about 175-200 Pa s, about 200-225 Pa s, about 225-250 Pa s, about 250-275 Pa s, or about 275-300 Pa s.
  • Shear strength and/or resistance are measurements of the ability of a material to resist external shear stress (i.e., shear load) without failure (i.e. loss of adhesion or integrity).
  • polymer compositions of the present disclosure can have a therapeutically effective shear strength.
  • a polymer composition can have a shear strength which provides for durable adhesion and high retention of the polymer composition on a target tissue of a subject.
  • a gel polymer composition of the present disclosure can have a shear strength which provides for durable adhesion and high retention of the polymer composition on a target tissue of a subject.
  • a gel polymer composition can have a shear strength which allows the polymer composition to retain its shape, adhesion, connectivity and/or consistency on the surface of a target tissue for one or more hours, one or more days, or one or more weeks.
  • a polymer composition can have shear strength from about 1 to about 360 kPa. In certain embodiments, the polymer composition can have shear strength from about 100-360 kPa. In certain embodiments, the polymer composition can have shear strength from about 200-360 kPa.
  • the polymer composition can have a shear strength from about 1-20 kPa, about 20-40 kPa, about 40-60 kPa, about 60- 80 kPa, about 80-100 kPa, about 100-120 kPa, about 120-140 kPa, about 140-160 kPa, about 160-180 kPa, about 180-200 kPa, about 200-220 kPa, about 220-240 kPa, about 240-260 kPa, about 260-280 kPa, about 280-300 kPa, about 300-320 kPa, about 320-340 kPa, or about 340- 360 kPa.
  • the shear strength of a polymer composition can be measured using ASTM F2255-05, or a modified Lap Shear test variation thereof.
  • the polymer composition comprises a gel.
  • a gel generally comprises a crosslinked polymeric framework which encompasses a network of pores filled with an interstitial solvent (e.g., a fluid).
  • the polymer composition comprises a hydrogel, wherein the interstitial fluid comprises water.
  • the polymer composition comprises an alcogel, wherein the interstitial fluid comprises an alcohol (e.g., methanol, ethanol).
  • Swelling i.e., an increase in volume
  • shrinkage i.e., a decrease in volume
  • the ability and/or tendency of a gel material to swell and/or shrink in certain solvent environments will depend on the chemical nature of the polymer and the solvent (e.g., solubility, hydrophobicity, pore structure, affinity) and the elasticity of the polymer network of the gel.
  • polymer compositions of the present disclosure can have a therapeutically effective swelling ratio and/or water content.
  • a polymer composition can have a swelling ratio and/or water content which provides for strong adhesion and high retention of the polymer composition on a target tissue of a subject.
  • a gel polymer composition of the present disclosure can have a swelling ratio and/or water content which provides for strong adhesion and high retention of the polymer composition on a target tissue of a subject.
  • a gel polymer composition can have a swelling ratio and/or water content which allows the polymer composition to retain its shape, adhesion, connectivity and/or consistency on the surface of a target tissue for one or more hours, one or more days, or one or more weeks.
  • a polymer composition can have a swelling ratio from about 5% to about 50%.
  • a polymer composition can have a swelling ratio of at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%.
  • a polymer composition can have a swelling ratio of no more than about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, or about 10%.
  • a polymer composition has a swelling ratio of about 25% or less, about 20% or less, about 15% or less, or about 10% or less.
  • a polymer composition can have a swelling ratio from about 1- 3%, about 3-6%, about 6-10%, about 1-5%, about 1-10%, about 5-10%, about 11-13%, about 13-16%, about 16-20%, about 10-20%, about 10-15%, about 15-20%, about 21-23%, about
  • a polymer composition can have a short-term swelling ratio (i.e., a swelling ratio measured for about 1 to 24 hours) from about 1-3%, about 3-6%, about 6-10%, about 1- 5%, about 1-10%, about 5-10%, about 11-13%, about 13-16%, about 16-20%, about 10-20%, about 10-15%, about 15-20%, about 21-23%, about 23-26%, about 26-30%, about 20-30%, about 20-25%, about 25-30%, about 31-33%, about 33-36%, about 36-40%, about 30-40%, about 30-35%, about 35-40%, about 41-43%, about 43-46%, about 46-50%, about 40-50%, about 40-45%, or about 45-50%.
  • a short-term swelling ratio i.e., a swelling ratio measured for about 1 to 24 hours
  • a polymer composition can have a medium -term swelling ratio (i.e., a swelling ratio measured for about 1 to 7 days) from about 1-3%, about 3-6%, about 6-10%, about 1-5%, about 1-10%, about 5-10%, about 11-13%, about 13-16%, about 16-20%, about 10-20%, about 10-15%, about 15-20%, about 21-23%, about 23-26%, about 26-30%, about 20-30%, about 20-25%, about 25-30%, about 31-33%, about 33-36%, about 36-40%, about 30-40%, about 30-35%, about 35-40%, about 41-43%, about 43-46%, about 46-50%, about 40-50%, about 40-45%, or about 45-50%.
  • a medium -term swelling ratio i.e., a swelling ratio measured for about 1 to 7 days
  • a polymer composition can have a long-term swelling ratio (i.e., a swelling ratio measured for about 1 to 4 weeks, or more) from about 1-3%, about 3-6%, about 6-10%, about 1-5%, about 1-10%, about 5-10%, about 11-13%, about 13-16%, about 16-20%, about 10-20%, about 10-15%, about 15-20%, about 21-23%, about 23-26%, about 26-30%, about 20-30%, about 20-25%, about 25-30%, about 31-33%, about 33-36%, about 36-40%, about 30-40%, about 30-35%, about 35-40%, about 41-43%, about 43-46%, about 46-50%, about 40-50%, about 40-45%, or about 45-50%.
  • a long-term swelling ratio i.e., a swelling ratio measured for about 1 to 4 weeks, or more
  • a hydrogel polymer composition can have a water content from about 5% to about 99%. In certain embodiments, a hydrogel polymer composition can have a water content from about 50% to about 99%. In certain embodiments, a hydrogel polymer composition can have a water content from about 65% to about 85%. In certain embodiments, a polymer composition can have a water content of at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80%.
  • a polymer composition can have a swelling ratio of about 99% or less, about 95% or less, about 90% or less, about 85% or less, about 80% or less, about 75% or less, about 70% or less, about 65% or less, about 60% or less, about 55% or less, about 50% or less, about 45% or less, about 40% or less, about 35% or less, or about 30% or less.
  • a polymer composition can have a water content from about 1-3%, about 3-6%, about 6-10%, about 1-5%, about 5-10%, about 1-10%, about 11-13%, about 13- 16%, about 16-20%, about 10-15%, about 15-20%, about 10-20%, about 21-23%, about 23- 26%, about 26-30%, about 20-25%, about 25-30%, about 20-30%, about 31-33%, about 33- 36%, about 36-40%, about 30-35%, about 35-40%, about 30-40%, about 41-43%, about 43- 46%, about 46-50%, about 40-45%, about 45-50%, about 40-50%, about 51-53%, about 53- 56%, about 56-60%, about 50-55%, about 55-60%, about 50-60%, about 61-63%, about 63- 66%, about 66-70%, about 60-65%, about 65-70%, about 60-70%, about 71-73%, about 73- 76%, about 76-80%, about 70-75%, about 75
  • a hydrogel polymer composition of the present disclosure permits controlled and sustained release of one or more therapeutic agents over a period of time.
  • the hydrogel polymer composition allows for the release of at least 1 pg/day, at least 2 pg/day, at least 3 pg/day, at least 4 pg/day, at least 5 pg/day, at least 6 pg/day, at least 7 pg/day, at least 8 pg/day, at least 9 pg/day, at least 10 pg/day, at least 11 pg/day, at least 12 pg/day, at least 13 pg/day, at least 14 pg/day, at least 15 pg/day, at least 16 pg/day, at least 17 pg/day, at least 18 pg/day, at least 19 pg/day, at least 20 pg/day, at least 25 pg/day, at least 30 pg/day, at least 35
  • polymer compositions of the present disclosure can have a therapeutically effective rate of polymeric degradation (i.e. degradation rate).
  • a polymer composition can have a degradation rate which provides for sustained adhesion and high retention of the polymer composition on a target tissue of a subject.
  • a gel polymer composition of the present disclosure can have a degradation rate which provides for sustained adhesion and high retention of the polymer composition on a target tissue of a subject.
  • a gel polymer composition can have a degradation rate which allows the polymer composition to retain its shape, adhesion, connectivity and/or consistency on the surface of a target tissue for one or more hours, one or more days, or one or more weeks.
  • a polymer composition can have a degradation rate from 1-50 days.
  • a polymer composition can have a degradation rate from about 1-3 days, about 3-6 days, about 6-10 days, about 1-5 days, about 1-10 days, about 5-10 days, about 11-13 days, about 13-16 days, about 16-20 days, about 10-20 days, about 10-15 days, about 15-20 days, about 21-23 days, about 23-26 days, about 26-30 days, about 20-30 days, about 20-25 days, about 25-30 days, about 31-33 days, about 33-36 days, about 36-40 days, about 30-40 days, about 30-35 days, about 35-40 days, about 41-43 days, about 43-46 days, about 46-50 days, about 40-50 days, about 40-45 days, or about 45-50 days.
  • the polymer compositions of the present disclosure have biocompatibility with a target tissue of a subject.
  • the biomechanical properties of the polymer compositions are similar and/or biocompatible to the biomechanical properties of a target tissue of a subject (e.g., the cornea of a subject).
  • the biocompatibility of a polymer compositions can be evidenced by low inflammatory response in a target tissue or subject. In certain embodiments, the biocompatibility of a polymer compositions can be evidenced by the survival rate of cells from a target tissue which are implanted or incorporated into a portion of the polymer composition.
  • polymer compositions of the present disclosure can be formed as molded, stamped, or shaped gel compositions. Molded, stamped or shaped hydrogels can be prepared using, for example, the methods set forth in US 20050008675 or US 20040258729, each of which is incorporated herein by reference in its entirety, insofar as each describes the composition, production (including molding), analysis and use of hydrogels, including acrylated gelatin polymeric compositions such as GelMA hydrogels.
  • polymer compositions (e.g., hydrogel polymer compositions) of the present disclosure can be formed into cylinders, each cylinder having a length and a diameter.
  • polymer compositions e.g., hydrogel polymer compositions
  • the polymer composition can be conformed to the shape of the target surface.
  • the polymer composition is conformed to the convex, concave, or curved shape of a target surface.
  • polymer compositions can be formed into cylindrical rods.
  • cylindrical rods or “rods” describe cylinders which have a cylinder-length at least 3-times (3x) the cylinder-diameter.
  • a cylindrical rod can have: a length of about 3 mm and a diameter of about 0.75 mm; or a length of about 2.5 mm and a diameter of about 0.75 mm.
  • hydrogel rods of the present disclosure can be about 3 mm in length and about 0.75 mm in diameter.
  • hydrogel rods of the present disclosure can be about 6 mm in length and about 0.75 mm in diameter.
  • polymer compositions can be formed into cylindrical disks.
  • “cylindrical disks” or “disks” describe cylinders which have a cylinder-diameter at least 2-times (2x) the cylinder-length.
  • a cylindrical disk can have: a length of about 2.5 mm and a diameter of about 6 mm; or a length of about 2 mm and a diameter of about 6 mm.
  • polymeric compositions of the present disclosure can be produced as described in the art, including Nichol et al., Biomaterials, 2010 Jul, 31(21): 5536-44; Assmann et al., Biomaterials, 2017, 140: 115-127; Noshadi et al., Biomater. Sci., 2017, 5: 2093-2105; each of which is incorporated herein by reference in its entirety, insofar as each describes the production of polymeric compositions, including acryloyl gelatin polymeric compositions such as GelMA hydrogels.
  • a polymer composition of the present disclosure can be formed by crosslinking two or more chemically modified gelatin components in a precursor polymer composition to form a gel polymer composition.
  • a polymer composition of the present disclosure can crosslink, polymerize and/or gel under wet, aqueous and/or biological conditions to form a gel polymer composition.
  • the crosslinking of the two or more chemically modified gelatin components is initiated, facilitated, or enabled when exposed to specific crosslinking conditions (e.g., acidic conditions, basic conditions, high-salt conditions, low salt conditions, high temperature, agitation, solubility conditions).
  • the crosslinking of the two or more chemically modified gelatin components is initiated, facilitated, or enabled by a crosslinking agent. In certain embodiments, the crosslinking of the two or more chemically modified gelatin components is initiated, facilitated, or enabled by a crosslinking agent under specific crosslinking conditions.
  • the present disclosure provides methods for producing a gel polymer composition, such as a hydrogel polymer composition.
  • the present disclosure provides methods for producing a Acrylated gelatin hydrogel polymer composition.
  • FIG. 2 provides a method 100 for producing a gel polymer composition.
  • a precursor polymer composition comprising chemically modified gelatin with crosslinkable groups (e.g., acryloyl-substituted gelatin, GelMA) is provided.
  • GelMA acryloyl-substituted gelatin
  • one or more additional chemically modified polymer precursors with cross-linkable groups e.g., MeHA
  • a solution comprising one or more crosslinking agents and/or photoinitiators is added to the precursor polymer composition.
  • a therapeutic agent, cell, and/or particle i.e., microparticle or nanoparticle
  • the precursor polymer composition is polymerized/crosslinked to produce a gel polymer composition.
  • methods for producing a gel polymer composition can include providing a precursor polymer composition comprising chemically modified gelatin with crosslinkable groups (e.g., acryloyl -substituted gelatin, GelMA).
  • the chemically modified gelatin comprises acrylated gelatin.
  • the chemically modified gelatin comprises gelatin methacryloyl (i.e. GelMA).
  • the precursor polymeric composition comprises one or more solvents or liquid vehicles, diluents, dispersion media, dispersing agents, granulating agents, binding agents, disintegrating agents, suspension agents, surface active agents, emulsifiers or emulsifying agents, isotonic agents, thickening agents, preservatives, solid binders, buffering agents, lubricants, coloring agents, coating agents, sweeteners, flavourings, perfuming agents, or combinations thereof.
  • the precursor polymeric composition comprises one or more solvents.
  • the solvent comprises an aqueous solvent.
  • aqueous solvents include, but are not limited to, distilled water, deionized water, saline, Dulbecco’s phosphate-buffered saline (DPBS), and Ringer’s solution.
  • the solvent comprises DPBS.
  • the solvent comprises an organic solvent.
  • organic solvents include, but are not limited to, hexanes, benzene, toluene, acetone, diethyl ether, chloroform, dichloromethane, isopropanol, methanol, ethanol, n-propanol, and n-butanol.
  • a precursor polymer composition can be in a sprayable form.
  • a precursor polymer composition can be in a high-viscosity form (e.g., paste-like viscosity).
  • a precursor polymer composition can be in a low-viscosity form (e.g., liquid-like viscosity).
  • methods for producing a gel polymer composition can include a step of adding one or more additional chemically modified polymer precursors with cross-linkable groups to the precursor polymer composition.
  • methods for producing a gel polymer composition can include: (i) providing a precursor polymer composition comprising chemically-modified gelatin with crosslinkable groups (e.g., acryloyl-substituted gelatin, GelMA); and (ii) adding one or more additional chemically-modified polymer precursors with cross-linkable groups to the precursor polymer composition.
  • methods for producing a gel polymer composition can include a step of adding one or more crosslinking agents and/or polymer crosslinking initiators (e.g., photoinitiators) to the precursor polymer composition.
  • methods for producing a gel polymer composition can include: (i) providing a precursor polymer composition comprising chemically modified gelatin with crosslinkable groups (e.g., acryloyl-substituted gelatin, GelMA); and (ii) adding one or more crosslinking agents and/or polymer crosslinking initiators (e.g., photoinitiators) to the precursor polymer composition.
  • methods for producing a gel polymer composition can include: (i) providing a precursor polymer composition comprising chemically-modified gelatin with crosslinkable groups (e.g., acryloyl-substituted gelatin, GelMA); (ii) adding one or more additional chemically-modified polymer precursors with cross-linkable groups to the precursor polymer composition; and (iii) adding one or more crosslinking agents and/or polymer crosslinking initiators (e.g., photoinitiators) to the precursor polymer.
  • crosslinkable groups e.g., acryloyl-substituted gelatin, GelMA
  • crosslinkable groups e.g., acryloyl-substituted gelatin, GelMA
  • crosslinkable groups e.g., acryloyl-substituted gelatin, GelMA
  • crosslinkable groups e.g., acryloyl-substituted gelatin, GelMA
  • crosslinkable groups e.g
  • one or more crosslinking agents and/or polymer crosslinking initiators can be added to the precursor polymer before one or more additional chemically modified polymer precursors with cross-linkable groups are added to the precursor polymer composition.
  • methods for producing a gel polymer composition can include: (i) providing a precursor polymer composition comprising chemically-modified gelatin with crosslinkable groups (e.g., acryloyl-substituted gelatin, GelMA); (ii) adding one or more crosslinking agents and/or polymer crosslinking initiators (e.g., photoinitiators) to the precursor polymer; and (iii) adding one or more additional chemically-modified polymer precursors with cross-linkable groups to the precursor polymer composition.
  • crosslinkable groups e.g., acryloyl-substituted gelatin, GelMA
  • crosslinking agents and/or polymer crosslinking initiators e.g., photoinitiators
  • a polymer composition comprises one or more polymer crosslinking initiators, (e.g., crosslinking initiator which forms free-radicals when exposed to specific polymer crosslinking conditions, such as acidic conditions, basic conditions, high- salt conditions, low salt conditions, high temperature, agitation, solubility conditions, and light exposure).
  • a polymer composition comprises one or more photo-initiator elements (i.e., a crosslinking initiator which is initiated or activated by absorbing a certain wavelength of light).
  • precursor polymer compositions of the present disclosure comprise one or more photo-initiator elements (i.e., a crosslinking initiator which is initiated or activated by visible light).
  • the photo-initiator element can be activated by exposure to light.
  • light exposure can activate the photo-initiator to form free-radicals, wherein the free radicals can result in bond formation between reactive groups in the composition, such as vinyl-bond crosslinking between methacrylate groups in a GelMA polymer composition.
  • FIG. 3 provides an example of a series of reactions to produce a GelMA hydrogel polymer composition, in which: (i) a photo-initiator element is activated by light energy (hv) to form free-radicals (R*), which then initiate bond formation between reactive groups on separate gelatin methacryloyl polymer precursors, thereby forming a crosslinked GelMA polymer network. The continued reaction between reactive groups on gelatin methacryloyl components will results in the formation of a broader GelMA hydrogel polymer composition.
  • a photo-initiator element can be activated by exposure to one or more light sources selected from visible light sources (e.g., white or blue light), ultraviolet (UV) light sources, near-infrared (NIR) light sources, and fluorescent light sources.
  • the photo-initiator element comprises a visible light- activated photo-initiator, such as a visible light-activated photo-initiator which is activated upon exposure to light having a wavelength from about 380 nm to about 740 nm.
  • the visible light-activated photo-initiator can be activated upon exposure to light having a wavelength of from about 380-435 nm (i.e., violet light), about 435-500 nm (i.e. blue light), about 500-565 nm (i.e. green light), about 565-600 nm (i.e. yellow light), about 600-650 nm (i.e. orange light), or about 650-740 nm (i.e. red light).
  • the photo-initiator element comprises an ultraviolet light-activated photoinitiator.
  • the photo-initiator element comprises a near-infrared (NIR) light-activated photo-initiator.
  • the photo-initiator element comprises a white light-activated photo-initiator.
  • the photo-initiator element comprises a blue light-activated photo-initiator.
  • methods for producing a gel polymer composition can include a step of adding one or more a therapeutic agent and/or particle (i.e., microparticle or nanoparticle) to the precursor polymer composition.
  • one or more a therapeutic agent and/or particle can be added to the precursor polymer before one or more additional chemically modified polymer precursors with cross-linkable groups are added to the precursor polymer composition.
  • one or more a therapeutic agent and/or particle can be added to the precursor polymer before one or more crosslinking agents and/or polymer crosslinking initiators (e.g., photoinitiators) are added to the precursor polymer composition.
  • methods for producing a gel polymer composition can include: (i) providing a precursor polymer composition comprising chemically-modified gelatin with crosslinkable groups (e.g., acryloyl-substituted gelatin, GelMA); (ii) optionally adding one or more additional chemically-modified polymer precursors with cross-linkable groups to the precursor polymer composition; (iii) adding one or more crosslinking agents and/or polymer crosslinking initiators (e.g., photoinitiators) to the precursor polymer; and (iv) optionally adding one or more therapeutic agent and/or particle.
  • crosslinkable groups e.g., acryloyl-substituted gelatin, GelMA
  • a precursor polymer composition can be clarified, purified, or processed for quality and/or purity prior to any polymerizing/crosslinking step.
  • a precursor polymer composition can be filtered.
  • a precursor polymer composition can be lyophilized.
  • a precursor polymer composition can be frozen for storage.
  • methods for producing a gel polymer composition can include a step of polymerizing/crosslinking the precursor polymer composition to produce a gel polymer composition.
  • methods for producing a gel polymer composition can include: (i) providing a precursor polymer composition comprising chemically-modified gelatin with crosslinkable groups (e.g., acryloyl-substituted gelatin, GelMA); (ii) optionally adding one or more additional chemically-modified polymer precursors with cross-linkable groups to the precursor polymer composition; (iii) adding one or more crosslinking agents and/or polymer crosslinking initiators (e.g., photoinitiators) to the precursor polymer; (iv) optionally adding one or more therapeutic agent and/or particle; and (v) polymerizing/crosslinking the precursor polymer composition to produce a gel polymer composition.
  • crosslinkable groups e.g., acryloyl-substituted gelatin, GelMA
  • crosslinkable groups e.g.,
  • the crosslinking of chemically modified gelatin components and any additional chemically modified polymer precursors is initiated, facilitated, or enabled by exposure to UV or visible light in the presence of a photoinitiator component.
  • exposure to UV or visible light in the presence of a photoinitiator causes acryloyl groups on one chemically modified gelatin molecule to react with acryloyl groups on other chemically modified gelatin molecules to crosslink the acryloyl-substituted gelatin components and produce a gel (e.g., hydrogel).
  • exposure to visible light in the presence of a photoinitiator causes methacryloyl groups on one methacryloyl gelatin molecule to react with methacryloyl groups on other methacryloyl gelatin molecules to crosslink the methacryloyl-substituted gelatin components and produce a gelatin methacryloyl (GelMA) hydrogel.
  • a photoinitiator causes methacryloyl groups on one methacryloyl gelatin molecule to react with methacryloyl groups on other methacryloyl gelatin molecules to crosslink the methacryloyl-substituted gelatin components and produce a gelatin methacryloyl (GelMA) hydrogel.
  • the polymer composition is exposed to a light source for a duration from 1-60 minutes. In certain embodiments, the polymer composition is exposed to a light source for a duration of 1 minute or more, 5 minutes or more, 10 minute or more, 15 minutes or more, 20 minute or more, 25 minutes or more, or 30 minutes or more. In certain embodiments, the polymer composition is exposed to a light source for a duration of 1 minute or less, 5 minutes or less, 10 minute or less, 15 minutes or less, 20 minute or less, 25 minutes or less, or 30 minutes or less, 35 minutes or less, or 40 minutes or less.
  • the polymer composition is exposed to a light source for a duration of about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, about 60 seconds, about 65 seconds, about 70 seconds, about 75 seconds, about 80 seconds, about 85 seconds, about 90 seconds, about 95 seconds, about 100 seconds, about
  • the polymer composition is exposed to a light source for a duration of from about 1-3 minutes, about 3-6 minutes, about 6-10 minutes, about 1-5 minutes, about 1-10 minutes, about 5-10 minutes, about 11-13 minutes, about 13-16 minutes, about 16-20 minutes, about 10-20 minutes, about 10-15 minutes, about 15-20 minutes, about 21-23 minutes, about 23-26 minutes, about 26-30 minutes, about 20-30 minutes, about 20-25 minutes, about 25-30 minutes, about 31-33 minutes, about 33-36 minutes, about 36-40 minutes, about 30-40 minutes, about 30-35 minutes, about 35-40 minutes, about 41-43 minutes, about 43-46 minutes, about 46-50 minutes, about 40-50 minutes, about 40-45 minutes, about 45-50 minutes, about 51-53 minutes, about 53-56 minutes, about 56-60 minutes, about 50-60 minutes, about 50-55 minutes, or about 55-60 minutes.
  • a polymer composition can have a thickness from about 1 pm to about 10000 pm. In certain embodiments, a polymer composition can have a thickness from about 1-50 pm, about 50-100 pm, about 100-150 pm, about 150-200 pm, about 200-250 pm, about 250-300 pm, about 300-350 pm, about 350-400 pm, about 400-450 pm, about 450- 400 m, about 400-450 pm, about 450-500 pm, about 500-550 pm, about 550-600 pm, about 600-650 pm, about 650-700 pm, about 700-750 pm, about 750-800 pm, about 800-850 pm, about 850-900 pm, about 900-950 pm, about 950-1000 pm, about 1000-1500 pm, about 1500-2000 pm, about 2000-2500 pm, about 2500-3000 pm, about 3000-3500 pm, about
  • a precursor polymer composition can be cooled prior to or during crosslinking reactions. In certain embodiments, a precursor polymer composition can be cooled to a temperature of from about 0°C and about 30°C prior to or during crosslinking reactions. In certain embodiments, a precursor polymer composition can be cooled to a temperature of from about 0-5°C, about 5-10°C, about 0-10°C, about 10-15°C, about 15- 20°C, about 10-20°C, about 20-25°C, about 25-30°C, or about 20-30°C. In certain embodiments, a precursor polymer composition can be heated prior to or during crosslinking reactions.
  • a precursor polymer composition can be heated to a temperature of from about 30°C and about 150°C prior to or during crosslinking reactions. In certain embodiments, a precursor polymer compositions can be heated to a temperature of from about 30-35°C, about 35-40°C, about 30-40°C, about 40-45°C, about 45-50°C, about 40-50°C, about 50-55°C, about 55-60°C, about 50-60°C, about 60-65°C, about 65-70°C, about 60-70°C, about 70-75°C, about 75-80°C, about 70-80°C, about 80-85°C, about 85- 90°C, about 80-90°C, about 90-95°C, about 95-100°C, about 90-100°C, about 100-105°C, about 105-110°C, about 100-110°C, about 110-115°C, about 115-120°C, about 110-120°C, about 130-135°C, about 135-140
  • a gel polymer composition can be dialyzed to remove any unreacted compounds from the gel mixture or structure.
  • a gel polymer composition can be dialyzed with a dialysis buffer that comprises deionized water.
  • a gel polymer composition can be filtered.
  • a gel polymer composition can be dried.
  • a gel polymer composition can be lyophilized.
  • a gel polymer composition can be frozen for storage.
  • polymer compositions of the present disclosure can be formed, molded, extruded woven, or otherwise produced or processed into fibers, films, discs, fabrics, tubes, conduits, rods, rings, mesh, or any other form or shape for polymeric or gel materials known in the art.
  • polymer compositions of the present disclosure can be formed, molded, extruded woven, or otherwise produced or processed into single layer structures or multi-layered structures (e.g., two layers, three layers, four layers, etc.).
  • a polymer composition of the present disclosure comprises macromolecular polymeric and/or fibrous elements which are interwoven or intertwined within the interstitial porous network of a polymer composition, but which are not chemically connected to the core crosslinked polymeric network.
  • macromolecules include polycaprolactone, gelatin, gelatin methacrylate, alginate, alginate methacrylate, chitosan, chitosan methacrylate, glycol chitosan, glycol chitosan methacrylate, hyaluronic acid, hyaluronic acid methacrylate, and other non-crosslinked natural or synthetic polymeric chains.
  • Gel materials which includes an interwoven macromolecular structure can be referred to as a composite structure or composite gel. Examples of hydrogel/fiber composites are described, for example, in Moutos et al. Nat.
  • a precursor polymer composition can be in a high-viscosity form (e.g., paste-like viscosity), and incorporated into a macromolecular polymeric matrix (e.g., fibrous mat or tissue matrix).
  • a precursor polymer composition can be in a low-viscosity form (e.g., liquid-like viscosity), and incorporated into a macromolecular polymeric matrix (e.g., fibrous mat or tissue matrix).
  • a cross-linked polymer composition can have a substantially covalent matrix form.
  • a cross-linked polymer composition can have an amorphous matrix form (i.e., matrix formed primarily through ionic and/or hydrogen bonding).
  • polymer compositions of the present disclosure can be formed as patterned gel compositions (e.g., a micropatterned hydrogel).
  • Micropatterned hydrogels can be prepared using, for example, the methods set forth in US 6,423,252, which is incorporated herein by reference in its entirety, insofar as it describes the composition, production (including micropatterning), analysis and use of hydrogels, including acrylated gelatin polymeric compositions such as GelMA hydrogels.
  • the method comprises: (i) contacting a precursor polymer composition with a mold or surface which comprises a three-dimensional negative configuration (i.e., template) of a micropattern; and (ii) crosslinking and/or polymerizing the precursor polymer composition to produce a crosslinked gel polymer composition (e.g., GelMA hydrogel) which includes the micropattern on at least on surface of the hydrogel.
  • a crosslinked gel polymer composition e.g., GelMA hydrogel
  • polymer compositions of the present disclosure can be formed as molded, stamped, or shaped gel compositions.
  • Molded, stamped or shaped hydrogels can be prepared using, for example, the methods set forth in US 20050008675 or US 20040258729, each of which is incorporated herein by reference in its entirety, insofar as each describes the composition, production (including molding), analysis and use of hydrogels, including acrylated gelatin polymeric compositions such as GelMA hydrogels.
  • Suturing, tissue transplantation, and the use of tissue adhesives are common treatments for defects and/or traumatic injuries to soft tissues (such as corneal or scleral tissues).
  • soft tissues such as corneal or scleral tissues.
  • each treatment carries risks and complications: (i) Suturing requires advanced surgical skill and early treatment, it often results in irregular stigmatisms, and can often lead to microbial entrapment and infection; (ii) Tissue grafting and transplantation require donor tissue (with associated high costs), advanced surgical skill, and present a high risk of immune reactions or full rejection of the grafted tissue; (iii) Tissue adhesives (such as cyanoacrylate glues, fibrin glues, or polyethylene-glycol (PEG)-based sealants) have limited effectiveness and adhesion (particularly in aqueous and physiological environments), have limited durability, can be difficult to apply and control texture, have a high probability of leaking, lack of biocompatibility (e.g., inflammatory) and possible toxicity, have a
  • polymer compositions of the present disclosure can be used as a sealant composition for treating or repairing soft tissue in a subject.
  • polymer compositions of the present disclosure can be used as a delivery vehicle for administering a therapeutic agent for treating or repairing soft tissue in a subject.
  • polymer compositions of the present disclosure can be used as a sealant composition for treating or repairing soft tissue in a subject, and as a delivery vehicle for administering a therapeutic agent for treating or repairing the soft tissue of the subject.
  • the methods and compositions of the present disclosure can be used to adhere, seal or treat target soft tissues of a subject.
  • the methods and compositions of the present disclosure can be used to adhere, seal or treat one or more target soft tissues selected from: adipose tissue, bladder tissue, bone marrow, cardiovascular tissue (e.g., cardiac), dura mater, endocrine glands, gastrointestinal tissue, hair follicles, kidney tissue, liver tissue, lung tissue, lymph nodes, muscle tissue, neural/nerve tissue (e.g., peripheral nervous system), ocular tissue (e.g., corneal), oral tissue (e.g., craniofacial, odontic, periodontic), pancreatic tissue, renal tissue, skin tissue (e.g., for treatment of topical ulcers, such as diabetic ulcers), urethra tissue, vascular tissue.
  • the methods and compositions of the present disclosure can be used to adhere, seal, or treat one or more target soft tissues in stressed and/or physiological environment, or similar applications which require elastic and/or adhesive compositions.
  • Polymer compositions e.g., Acrylated gelatin polymer compositions
  • Polymer compositions may be administered by any route which results in a therapeutically effective outcome.
  • the method includes applying a pre-gelation polymer composition to an applicator; placing the applicator containing the pre-gelation polymer composition onto a surface of the target tissue of the subject; and crosslinking (e.g., photocrosslinking) the polymer composition by exposing the pre-gelation polymer composition to crosslinking conditions (e.g., visible light with a photoinitiator).
  • the pre-gelation polymer composition is applied directly to the surface of the target tissue without an applicator.
  • application to the surface of a target tissue comprises application to an external surface of a target tissue (e.g., topical application).
  • application to the surface of a target tissue comprises application/inj ection to a space directly below the surface of a target tissue (e.g., subconjunctival application to ocular tissue, subretinal application to ocular tissue).
  • a target soft tissue can be treated or sealed by applying a first layer which comprises a first polymer composition of the present disclosure which is engineered to have specific physical, mechanical, structural, chemical and/or biological properties (e.g., elasticity, biodegradability, porosity); and then applying a second layer which comprises a second polymer composition which is engineered to have different physical, mechanical, structural, chemical and/or biological properties (e.g., elasticity, biodegradability, porosity).
  • a first layer which comprises a first polymer composition of the present disclosure which is engineered to have specific physical, mechanical, structural, chemical and/or biological properties (e.g., elasticity, biodegradability, porosity)
  • a second layer which comprises a second polymer composition which is engineered to have different physical, mechanical, structural, chemical and/or biological properties (e.g., elasticity, biodegradability, porosity).
  • the method can include applying one or more additional layers (e.g., a third layer, a fourth layer, etc.), each of which comprises a polymer composition of the present disclosure which is engineered to have specific physical, mechanical, structural, chemical and/or biological properties (e.g., elasticity, biodegradability, porosity).
  • additional layers e.g., a third layer, a fourth layer, etc.
  • each of which comprises a polymer composition of the present disclosure which is engineered to have specific physical, mechanical, structural, chemical and/or biological properties (e.g., elasticity, biodegradability, porosity).
  • a target soft tissue can be treated by: (i) forming a preformed polymer composition by polymerizing a polymer composition of the present disclosure; and (ii) applying the pre-formed polymer composition onto a surface or under the surface (e.g., subconjunctival, subretinal) of the target tissue of the subject.
  • application to the surface of a target tissue comprises application/inj ection to a space directly below the surface of a target tissue (e.g., subconjunctival application to ocular tissue, subretinal application to ocular tissue).
  • the pre-formed polymer composition can be engineered to have specific physical, mechanical, structural, chemical and/or biological properties (e.g., elasticity, biodegradability, porosity).
  • a target soft tissue can be treated by: (i) forming a preformed hydrogel polymer composition by polymerizing a polymer composition of the present disclosure; (ii) drying the hydrogel polymer by removing a substantial portion of interstitial fluid from the hydrogel (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90 %, or at least 95% of interstitial fluid); (iii) applying the pre-formed polymer composition onto a surface or under the surface (e.g., subconjunctival, subretinal) of the target tissue of the subject; and (iv) optionally rehydrating the dried hydrogel polymer to a substantially hydrated form (e.g., e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90 %, or at least 95% of interstitial fluid volume).
  • a substantially hydrated form e.g., e.g., at least 50%, at least 60%, at least 70%,
  • application to the surface of a target tissue comprises application/inj ection to a space directly below the surface of a target tissue (e.g., subconjunctival application to ocular tissue, subretinal application to ocular tissue).
  • the pre-formed polymer composition can be engineered to have specific physical, mechanical, structural, chemical and/or biological properties (e.g., elasticity, biodegradability, porosity).
  • polymer compositions of the present disclosure can be prepared as, or comprised in, therapeutic compositions.
  • hydrogel polymer compositions of the present disclosure can be prepared as, or comprised in, therapeutic compositions.
  • acrylated gelatin hydrogel polymer compositions of the present disclosure can be prepared as, or comprised in, therapeutic compositions.
  • Such compositions comprise one or more polymer composition of the present disclosure (including, optionally, one or more therapeutic agents or active ingredients) and one or more therapeutically acceptable excipients (e.g., carrier, solvent, or delivery vehicle).
  • Relative amounts of the polymer compositions may vary, depending upon the identity, size, and/or condition of the subject or tissue being treated and further depending upon the route by which the composition is to be administered or applied.
  • a therapeutic composition comprises from 0.1% and 99% (w/v) of a polymer composition of the present disclosure in the volume of the therapeutic composition.
  • a therapeutic composition comprises a polymer composition of the present disclosure at weight-per-volume concentration (w/v) of about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 56%, about 5
  • a therapeutic composition comprises a polymer composition of the present disclosure at weight-per-volume concentration (w/v) of from about 1-3%, about 3-6%, about 6-10%, about 1-5%, about 5-10%, about 1-10%, about 11-13%, about 13-16%, about 16- 20%, about 10-15%, about 15-20%, about 10-20%, about 21-23%, about 23-26%, about 26- 30%, about 20-25%, about 25-30%, about 20-30%, about 31-33%, about 33-36%, about 36- 40%, about 30-35%, about 35-40%, about 30-40%, about 41-43%, about 43-46%, about 46- 50%, about 40-45%, about 45-50%, about 40-50%, about 51-53%, about 53-56%, about 56-
  • w/v weight-per-volume concentration
  • therapeutic compositions and formulations of the present disclosure comprises, without limitation, saline, liposomes (e.g., unilamellar vesicles, multilamellar vesicles), lipid particles (including microparticles and nanoparticles), and/or polymeric particles (including microparticles and nanoparticles).
  • therapeutic compositions and formulations of the present disclosure comprises a polymeric composition of the present disclosure which incorporates, without limitation, saline, liposomes, lipid particles (including microparticles and nanoparticles), polymeric particles (including microparticles and nanoparticles) or a combination thereof.
  • therapeutic compositions and formulations of the present disclosure are aqueous formulations (i.e., formulations which comprise water).
  • therapeutic compositions and formulations of the present disclosure comprise water, sanitized water, or Water-for-inj ection (WFI).
  • WFI Water-for-inj ection
  • therapeutic compositions and formulations of the present disclosure comprises one or more of the following: pH buffered solutions (e.g., phosphate buffered saline (PBS), HEPES, TES, MOPS), isotonic saline, Ringer’s solution, Balanced Salt Solution Plus (BSS+, Alcon), polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol), alginic acid, ethyl alcohol, and therapeutically acceptable mixtures thereof.
  • PBS phosphate buffered saline
  • HEPES HEPES
  • TES TES
  • MOPS isotonic saline
  • Ringer solution
  • BSS+ Balanced Salt Solution Plus
  • polyols e.g., glycerol, propylene glycol, liquid polyethylene glycol
  • alginic acid ethyl alcohol
  • therapeutically acceptable mixtures thereof e.glycerol, propylene glycol, liquid polyethylene glycol
  • Formulations of the present disclosure can be used in any step of producing, processing, preparing, storing, expanding, or administering polymer compositions of the present disclosure.
  • compositions of the present disclosure comprise one or more therapeutically acceptable excipient (e.g., a vehicle capable of suspending or dissolving the polymeric compound.
  • Excipients may include, for example: anti adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspension, or dispersing agents, sweeteners, and waters of hydration.
  • excipients include, but are not limited to: acetic acid, aluminum stearate, butylated hydroxytoluene (BHT), calcium carbonate, calcium chloride, calcium phosphate (dibasic), calcium stearate, carboxymethyl celluloses, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, glucose, glucuronic acid, gluconic acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyl-butanedioic acid, inosite, lactose, magnesium chloride, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, phosphoric acid, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palm
  • the polymer compositions of the present disclosure can include a therapeutic agent. In certain embodiments, the polymer compositions of the present disclosure can include a therapeutic agent as a delivery payload.
  • a polymer composition of the present disclosure can include a therapeutic agent at a concentration (w/v) from about 0% and about 40%.
  • a precursor polymer composition of the present disclosure can include a therapeutic agent at a concentration (w/v) from about 0% and about 40%.
  • a gel polymer composition of the present disclosure can include a therapeutic agent at a concentration (w/v) from about 0% and about 40%.
  • a polymer compositions of the present disclosure can include a therapeutic agent at a concentration (w/v) from about 1-2%, about 2-4%, about 4-6%, about 6-8%, about 8-10%, about 1-5%, about 5-10%, about 1-10%, about 10-12%, about 12-14%, about 14-16%, about 16-18%, about 18-20%, about 10-15%, about 15-20%, about 10-20%, about 20-22%, about
  • a precursor polymer composition of the present disclosure can include a therapeutic agent at a concentration from about 0.1 mg/mL and about 500 mg/mL.
  • a polymer compositions of the present disclosure can include a therapeutic agent at a concentration from about 0.1-0.5 mg/mL, about 0.5-1.0 mg/mL, about 1.0-2.5 mg/mL, about 2.5-5.0 mg/mL, about 5.0-10.0 mg/mL, about 10.0-25.0 mg/mL, about 25.0-50.0 mg/mL, about 50.0-100.0 mg/mL, about 100-150 mg/mL, about 150-200 mg/mL, about 200-250 mg/mL, about 250-300 mg/mL, about 300-350 mg/mL, about 350-400 mg/mL, about 400-450 mg/mL, about 450-500 mg/mL, about 500-550 mg/mL, about 550-600 mg/mL, about 600-650 mg/mL, about 650-
  • a polymer composition can deliver a therapeutic agent to a peak concentration in less than 1 hour. In certain embodiments, a polymer composition can deliver a therapeutic agent to a peak concentration in less than 1 day. In certain embodiments, a polymer composition can deliver a therapeutic agent to a peak concentration in from about 0-2 hours, about 2-4 hours, about 4-6 hours, about 6-8 hours, about 8-10 hours, about 10-12 hours, about 12-16 hours, about 16-20 hours, about 20-24 hours, about 24-30 hours, about 30-36 hours, about 36-42 hours, or about 42-48 hours. In certain embodiments, a polymer composition can deliver a therapeutic agent to a peak concentration in less than 1 week.
  • a polymer composition can deliver a therapeutic agent to a peak concentration in from about 0-2 days, about 2-4 days, about 4-6 days, about 6-8 days, about 8-10 days, about 10-12 days, about 12-16 days, about 16-20 days, about 20-24 days, about 24-30 days, about 30-35 days, about 35-40 days, about 40-45 days, about 45-50 days, about 50-55 days, or about 55-60 days.
  • a polymer composition can deliver a therapeutic agent to a peak concentration in less than 1 month.
  • a polymer composition can deliver a therapeutic agent to a peak concentration in less than 12 months.
  • a polymer composition can deliver a therapeutic agent to a peak concentration in from about 0-1 months, about 1-2 months, about 2-3 months, about 3-4 months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8 months, about 8-9 months, about 9-10 months, about 10-11 months, or about 11-12 months.
  • the therapeutic agent comprises one or more of a growth factor, a hemostatic agent, analgesics, anesthetics, antifungals, antibiotics, antibacterials, antiinflammatories, antimicrobials, anthelmintics, antidotes, antiemetics, antihistamines, antihypertensives, antimalarials, antipsychotics, antipyretics, antiseptics, antiarthritics, antituberculotics, antitussives, antivirals, cardioactive drugs, cathartics, chemotherapeutic agents, a colored or fluorescent imaging agent, corticoids (such as steroids), antidepressants, depressants, diagnostic aids, diuretics, enzymes, expectorants, hormones, hypnotics, immunosuppressants, minerals, nutritional supplements, parasympathomimetics, potassium supplements, radiation sensitizers, a radioisotope, sedatives, sulfonamides, stimulants, sympathom
  • the therapeutic agent comprises one or more anti- acanthamoebal, antiviral and/or antibacterial agents.
  • the therapeutic agent comprises one or more agent selected from acyclovir, valacyclovir, famciclovir, penciclovir, trifluridine, vidarabine, hydroxychloroquine, gatifloxacin, daptomycin, tigecycline, telavancin, chloramphenicol, fusidic acid, chlorohexidine, polyhexamethylene biguanide, propamidine, hexamidine, bacitracin, metronidazole, rifampin, ethambutol, streptomycin, isoniazid, silver nanoparticles, copper oxide nanoparticles, glycopeptides (e.g., teicoplanin, vancomycin), aminoglycosides (e.g., gentamycin, tobramycin, amikacin,
  • the therapeutic agent comprises one or more anti-fungal agents.
  • the therapeutic agent comprises one or more agent selected from amphotericin B, natamycin, candicin, fllipin, hamycin, nystatin, rimocidin, voriconazole, imidazoles, triazoles, thiazoles, allylamines, echinocandins, benzoic acid, ciclopirox, flucytosine, griseofulvin, haloprogin, tolnaftate, undecylenic acid, and povidone iodine, or a combination thereof.
  • the therapeutic agent comprises one or more antimicrobial agents.
  • the therapeutic agent comprises one or more antimicrobial agents selected from polymyxin B, vancomycin, cholera toxin, diphtheria toxin, lysostaphin, hemolysin, bacitracin, boceprevir, albavancin, daptomycin, enfuvirtide, oritavancin, teicoplanin, telaprevir, telavancin, guavanin 2, Maximin H5, derm ci din, cecropins, andropin, moricin, ceratotoxin, melittin, magainin, dermaseptin, brevinin-1, esculentins, buforin II, CAP18, LL37, baecin, apidaecins, prophenin, indolicidin, antimicrobial peptide (AMP) (e.g., Tet213), chlorhe
  • AMP antimicrobial peptide
  • the therapeutic agent comprises one or more antiinflammatory agents.
  • the therapeutic agent comprises one or more anti-inflammatory agent selected from steroidal anti-inflammatory drugs (e.g., prednisolone), corticosteroids (e.g., loteprednol etabonate), salicylates, non-steroidal anti-inflammatory drugs (e.g., bromfenac), mTOR inhibitors, calcineurin inhibitors, synthetic or natural antiinflammatory proteins, dexamethasone, 5 -fluorouracil, daunomycin, paclitaxel, curcumin, resveratrol, mitomycin, methylprednisolone, prednisolone, hydrocortisone, fludrocortisone, prednisone, celecoxib, ketorolac, piroxicam, diclorofenac, ibuprofen, and ketoprofen, rapamycin, cyclosporin, tacroli
  • steroidal anti-inflammatory drugs e
  • the therapeutic agent comprises one or more growth factors.
  • the therapeutic agent comprises a growth factor which comprises a recombinant hepatocyte growth factor or recombinant nerve growth factor.
  • the therapeutic agent comprises one or more growth factors selected from Activins (e.g., Activin A, Activin B, Activin AB), Adrenomedullin (AM), albumin, alpha-2 macroglobulin, annexin, Angiopoietin (Ang), Artemin, Autocrine motility factor, Bone morphogenetic proteins (BMPs) (e g., BMP-1, BMP -2, BMP-3, BMP -4, BMP-5, BMP- 6, BMP-7, BMP-8, BMP-9), Brain-derived neurotrophic factor (BDNF), Ciliary neurotrophic factor family, Ciliary neurotrophic factor (CNTF), connective tissue activated peptides (CTAPs), Epidermal growth factor (EGF
  • the therapeutic agent comprises one or hormone.
  • the therapeutic agent comprises one or more hormones selected from: antimullerian hormone, mullerian inhibiting factor or hormone), adiponectin, adrenocorticotropic hormone, corticotropin, angiotensinogen, angiotensin, antidiuretic hormone, vasopressin, arginine vasopressin, atrial -natriuretic peptide, atriopeptin, calcitonin, cholecystokinin, corticotropin-releasing hormone, erythropoietin, follicle-stimulating hormone, gastrin, ghrelin, glucagon, gonadotropin-releasing hormone, growth hormone- releasing hormone, human chorionic gonadotropin, human placental lactogen, growth hormone, somatomedin, leptin, luteinizing hormone, melanocyte stimulating hormone, orexin, oxyto
  • a polymer composition of the present disclosure can include one or more growth factors at a concentration (w/v) from about 0.001 pg/mL and about 2 g/mL. In certain embodiments, a polymer composition of the present disclosure can include one or more growth factors at a concentration (w/v) from about 0.001 pg/mL and about 1000 pg/mL. In certain embodiments, a polymer composition can include one or more growth factors at a concentration (w/v) from about 0.01 pg/mL and about 500 pg/mL.
  • a polymer composition can include one or more growth factors at a concentration (w/v) from about 0.1 pg/mL and about 200 pg/mL. In certain embodiments, a polymer compositions can include one or more growth factors at a concentration (w/v) from about 0.1-0.5 pg/mL, about 0.5-1.0 pg/mL, about 1-2 pg/mL, about 2-4 pg/mL, about 4-6 pg/mL, about 6-8 pg/mL, about 8-10 pg/mL, about 10-12 pg/mL, about 12-14 pg/mL, about 14-16 pg/mL, about 16-18 pg/mL, about 18-20 pg/mL, about 20-22 pg/mL, about 22-24 pg/mL, about 24-26 pg/mL, about 26-28 pg/mL, about 28-30 pg/mL, about 30-35 pg
  • 900-950 pg/mL about 950-1000 pg/mL, about 1000-1100 pg/mL, about 1100-1200 pg/mL, about 1200-1300 pg/mL, about 1300-1400 pg/mL, about 1400-1500 pg/mL, about 1500- 1600 pg/mL, about 1600-1700 pg/mL, about 1700-1800 pg/mL, about 1800-1900 pg/mL, or about 1900-2000 pg/mL.
  • the therapeutic agent comprises one or more hemostatic agents (i.e., a material that promotes hemostasis) and/or immunosuppressive agents.
  • the therapeutic agent comprises one or more agents selected from blood platelets, platelet-like nanoparticles (e.g., silicate nanoparticles), blood coagulation factors (e.g., thrombin, prothrombin), alkylating agents, antimetabolites, mycophenolate, cyclosporine, tacrolimus, rapamycin, or combinations thereof.
  • the therapeutic agent comprises an anticoagulant or blood thinner (e.g., heparin).
  • a polymer composition of the present disclosure can incorporate or be coated with cells or cell -precursors of a target tissue.
  • a polymer compositions can incorporate or be coated with one or more cells or cell-precursors of a target tissue selected from nerve cells, muscle cells, myocytes, cardiomyocytes, hepatocytes, keratinocytes, melanocytes, ameloblasts, fibroblasts, preosteoblasts, osteoblasts, osteoclasts, endothelial cells, epithelial cells, mesenchymal stem cells, neurolemmocytes (i.e., Schwann cells), embryonic stem cells, adult stem cells, pluripotent stem cells, multipotent stem cells, hematopoietic stem cells, adipose derived stem cells, bone marrow derived stem cells, osteocytes, neurocytes, or a combination thereof.
  • neurolemmocytes i.e., Schwann cells
  • embryonic stem cells adult
  • a polymer composition can incorporate or be coated with endothelial cells (e.g., corneal endothelial cells).
  • a polymer composition can incorporate or be coated with ocular cells.
  • a polymer composition can incorporate or be coated with adherent cell types (i.e., cells that form cell-to-cell network, 3D vasculature).
  • adherent cell types i.e., cells that form cell-to-cell network, 3D vasculature.
  • a polymer composition can incorporate or be coated with monolayer cell types (i.e., 2D).
  • a polymer composition can incorporate or be coated with epithelial cells, endothelial cells, keratocytes, and combinations thereof.
  • a polymer composition can incorporate or be coated with human umbilical vein endothelial cells (HUVEC) or vascular endothelial cells.
  • a polymer composition can incorporate or be coated with human retinal pigment epithelium cells (HRPEC), human neuroepithelial cells, human photoreceptor cells, human corneal endothelial cells, human neural crest cells, human retinal ganglion cells, human limbal cells, human cardiomyocytes, human hepatocytes, human dermal cells, human gastrointestinal epithelial cells, human neurons, and human islet cells, human immune cells, and other therapeutic human cells.
  • HRPEC human retinal pigment epithelium cells
  • human neuroepithelial cells human photoreceptor cells
  • human corneal endothelial cells human neural crest cells
  • human retinal ganglion cells human limbal cells
  • human cardiomyocytes human hepatocytes
  • human dermal cells human gastrointestinal epithelial cells
  • human neurons and human islet cells, human immune cells, and
  • cells or cell -precursors can be incorporated into or onto a polymer gel matrix by placing the polymer gel composition in a cell culture mixture for a duration of time.
  • the culture time may differ depending upon the cells used, but can generally be 1 to 21 days.
  • exposure of the polymer gel composition to cell cultures is repeated to increase the cell density in or on the gel matrix.
  • a polymer composition of the present disclosure can incorporate cells or cell-precursors according to the procedures disclosed in WO 2013040559; or Loessner et al., Nature protocols. 2016 Apr; 11(4): 727; each of which is incorporated herein by reference in its entirety, insofar as each describes the incorporation of cells or cell-precursors onto or into a gel matrix, such as an acrylated gelatin hydrogel.
  • polymer compositions of the present disclosure can be used as a sealant and/or therapeutic composition for treating and/or repairing soft tissue in a subject.
  • polymer compositions of the present disclosure can be used as a delivery vehicle for administering a therapeutic agent for treating and/or repairing soft tissue in a subject.
  • polymer compositions of the present disclosure can be used as a sealant and/or therapeutic composition for treating and/or repairing soft tissue in a subject, and as a delivery vehicle for administering a therapeutic agent for treating and/or repairing the soft tissue of the subject.
  • the methods and compositions of the present disclosure can be used to adhere, seal or treat one or more target soft tissues selected from ocular tissue (i.e. eyes), lung, cardiovascular, skin, kidney, bladder, urethra, dura mater, liver, gastrointestinal, or oral (i.e. mouth) tissue.
  • the methods and compositions of the present disclosure can be used to adhere, seal or treat one or more target soft tissues in a stressed and/or physiological environment, or similar applications which require elastic and/or adhesive compositions.
  • the present disclosure provides methods for treating and/or repairing soft tissue in a subject using polymer compositions of the present disclosure. In certain embodiments, the present disclosure provides methods for treating and/or repairing a defect, injury, and/or disease in the soft tissue of a subject using polymer compositions of the present disclosure.
  • the method includes: applying a pre-gelation polymer composition of the present disclosure (e.g., a polymer composition comprising acryloyl-substituted gelatin) to an applicator; placing the applicator containing the pregelation polymer composition onto a surface of a target soft tissue of the subject (e.g., location of soft tissue defect, injury, and/or disease); and crosslinking (e.g., photocrosslinking) the polymer composition by exposing the pre-gelation polymer composition to a crosslinking initiator (e.g., photoinitiator and visible light).
  • a pre-gelation polymer composition of the present disclosure e.g., a polymer composition comprising acryloyl-substituted gelatin
  • crosslinking e.g., photocrosslinking
  • the method includes removing the applicator from the gel polymer composition and/or soft tissue surface after the polymeric crosslinking and/or gelation of the polymer composition is complete.
  • the pre-gelation polymer composition is applied directly to the surface of the target soft tissue without an applicator.
  • the pre- gelation polymer composition is applied on or near (e.g., on the same tissue or under the tissue) the target soft tissue.
  • the pre-gelation polymer composition can have a strong, sustained adhesion and high retention on the target soft tissue of the subject.
  • the gel polymer composition can have a strong, sustained adhesion and high retention on the target soft tissue of the subject.
  • the polymer composition is engineered to present physical, mechanical, structural, chemical and/or biological properties (elasticity, water content) to match or resemble the target soft tissue.
  • the polymer composition is engineered to distribute a therapeutic agent to the target soft tissue.
  • the shear thinning property of the polymer composition is utilized to deliver the polymer composition.
  • a polymer composition can improve the cell viability once injected into the soft tissue.
  • the polymer composition is a scaffold for cells, wherein the function of the transplanted cells is improved through (i) direct action of the cells, (ii) supporting a secondary cell type for treating injuries, defects, or diseases of the soft tissue.
  • the polymer composition improves the structure of restored tissue to recapitulate naturally occurring tissues.
  • polymer compositions of the present disclosure can be used as a sealant and/or therapeutic composition for treating and/or repairing ocular soft tissue in the eye of a subject.
  • polymer compositions of the present disclosure can be used as a sealant and/or therapeutic composition for treating and/or repairing an ocular defect, ocular surface injury, or an ocular disease in the eye of a subject.
  • the ocular defect, injury or disease is a corneal or scleral defect, injury or disease.
  • the corneal or scleral injury is a laceration (partial- or full-thickness), perforation, incision (e.g., surgical incision), or similar surface trauma (such as trauma from a foreign object or projectile).
  • the ocular defect, injury or disease is an ocular ulcer, such as a corneal ulcer from severe infections, injuries, perforations, or other defects.
  • the target soft tissue is ocular tissue; optionally subconjunctival ocular tissue or retinal ocular tissue.
  • the present disclosure provides methods for treating an ocular defect, ocular surface injury, or an ocular disease in a subject with the polymer compositions of the present disclosure.
  • the method includes applying a pre-gelation polymer composition of the present disclosure (e.g., a polymer composition comprising acryloyl-substituted gelatin) to an applicator; placing the applicator containing the pre-gelation polymer composition onto a surface of the eye of the subject; and crosslinking (e.g., photo-crosslinking) the polymer composition by exposing the pre-gelation polymer composition to a crosslinking initiator (e.g., visible light).
  • a pre-gelation polymer composition of the present disclosure e.g., a polymer composition comprising acryloyl-substituted gelatin
  • crosslinking e.g., photo-crosslinking
  • the method includes removing the applicator from the gel polymer composition and/or ocular surface after the polymeric crosslinking and/or gelation of the polymer composition is complete.
  • the pre-gelation polymer composition is applied directly to the surface of the target ocular tissue without an applicator.
  • the pre-gelation polymer composition can have a strong, sustained adhesion and high retention on the ocular tissue of the subject.
  • the gel polymer composition can have a strong, sustained adhesion and high retention on the ocular tissue of the subject.
  • the polymer composition is engineered to present physical, mechanical, structural, chemical and/or biological properties (elasticity, water content) to match or resemble the target ocular tissue (e.g., corneal tissue).
  • the applicator is a curved, concave surface.
  • the applicator is a curved lens (e.g., contact lens).
  • the curvature of the applicator is similar to the curvature of the target ocular surface.
  • an ocular defect, ocular surface injury, or an ocular disease in a target ocular tissue can be treated by: (i) forming a pre-formed polymer composition by polymerizing a polymer composition of the present disclosure; and (ii) applying the pre-formed polymer composition onto a surface or under the surface (e.g., subconjunctival, subretinal) of the target tissue of the subject.
  • application to the surface of a target tissue comprises application/inj ection to a space directly below the surface of a target tissue (e.g., subconjunctival application to ocular tissue, subretinal application to ocular tissue).
  • the pre-formed polymer composition can be engineered to have specific physical, mechanical, structural, chemical and/or biological properties (e.g., elasticity, biodegradability, porosity).
  • an ocular defect, ocular surface injury, or an ocular disease in a target ocular tissue can be treated by: (i) forming a pre-formed hydrogel polymer composition by polymerizing a polymer composition of the present disclosure; (ii) drying the hydrogel polymer by removing a substantial portion of interstitial fluid from the hydrogel (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90 %, or at least 95% of interstitial fluid); (iii) applying the pre-formed polymer composition onto a surface or under the surface (e.g., subconjunctival, subretinal) of the target tissue of the subject; and (iv) optionally rehydrating the dried hydrogel polymer to a substantially hydrated form (e.g., e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90 %, or at least 95% of interstitial fluid volume).
  • a substantially hydrated form e
  • application to the surface of a target tissue comprises application/inj ection to a space directly below the surface of a target tissue (e.g., subconjunctival application to ocular tissue, subretinal application to ocular tissue).
  • the pre-formed polymer composition can be engineered to have specific physical, mechanical, structural, chemical and/or biological properties (e.g., elasticity, biodegradability, porosity).
  • the polymer composition improves (i) RPE monolayer formation, (ii) RPE function through preservation of photoreceptor structure and function, or (i) and (ii). In certain embodiments, the polymer composition restores or maintains vision. Oral Injuries and Diseases
  • polymer compositions of the present disclosure can be used as a sealant and/or therapeutic composition for treating and/or repairing soft tissue in the mouth of a subject.
  • polymer compositions can be used for treating and/or repairing oral tissue associated with periodontal diseases, injuries or ailments.
  • the periodontal disease, injury or ailment can include those associated with periodontal implants, including peri-implant diseases (PIDs) such as peri-implant mucositis (PIM) and peri-implantitis (PI).
  • PIDs peri-implant diseases
  • PIM peri-implant mucositis
  • PI peri-implantitis
  • polymer compositions of the present disclosure can be used to seal an area of soft tissue surrounding a periodontal implant.
  • polymer compositions of the present disclosure can be used to deliver a therapeutic agent (e.g., antimicrobial or anti-inflammatory) to an area of soft tissue surrounding a periodontal implant.
  • the polymer compositions comprise an osteoinductive agent.
  • the polymer compositions comprise one or more osteoinductive agents selected from silicate nanoparticles (SNs), calcium salts, bioglass, hydroxyapatite, demineralized bone matrix (DBM), or combinations thereof.
  • the polymer compositions comprise one or more silicate nanoparticles, including SNs that include one or more metals, such as calcium, aluminum, silver, gold, platinum, palladium, lithium, magnesium, sodium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, iridium, or combinations thereof.
  • the silicate nanoparticles include laponite nanoparticles.
  • the polymer compositions comprise one or more calcium salts, such as calcium phosphate, calcium sulfate, calcium hydroxide, calcium bromide, calcium fluoride, calcium iodide, calcium hydride, or combinations thereof.
  • the present disclosure provides methods for treating a defect, injury, or disease in the oral soft tissue of a subject, with the polymer compositions of the present disclosure.
  • the method includes: applying a pre-gelation polymer composition of the present disclosure (e.g., a polymer composition comprising acryloyl-substituted gelatin) to an applicator; placing the applicator containing the pregelation polymer composition onto a surface of the oral soft tissue of the subject (e.g., soft tissue surrounding a periodontal implant); and crosslinking (e.g., photo-crosslinking) the polymer composition by exposing the pre-gelation polymer composition to a crosslinking initiator (e.g., visible light).
  • a pre-gelation polymer composition of the present disclosure e.g., a polymer composition comprising acryloyl-substituted gelatin
  • crosslinking e.g., photo-crosslinking
  • the method includes removing the applicator from the gel polymer composition and/or oral soft tissue surface after the polymeric crosslinking and/or gelation of the polymer composition is complete.
  • the pre-gelation polymer composition is applied directly to the surface of the target oral soft tissue without an applicator.
  • the pre-gelation polymer composition can have a strong, sustained adhesion and high retention on the oral soft tissue of the subject.
  • the gel polymer composition can have a strong, sustained adhesion and high retention on the oral soft tissue of the subject.
  • the polymer composition is engineered to present physical, mechanical, structural, chemical and/or biological properties (elasticity, water content) to match or resemble the target oral soft tissue (e.g., soft tissue surrounding a periodontal implant).
  • polymer compositions of the present disclosure can be used as a sealant and/or therapeutic composition for treating and/or repairing soft tissue in the nervous system (e.g., central nervous system (CNS), peripheral nervous system (PNS)) of a subject.
  • the nervous system e.g., central nervous system (CNS), peripheral nervous system (PNS)
  • polymer compositions can be used for treating and/or repairing nerve tissue associated with traumatic injury or surgical damage, including Peripheral Nerve Injuries (PNI).
  • PNI Peripheral Nerve Injuries
  • Typical surgical interventions for these ailments are often associated with inflammation, heightened foreign body response (FBR), scaring, slower nerve regeneration, or loss of nerve function (partial or complete).
  • nerve tissue can be treated or sealed by applying a polymer composition of the present disclosure to the target nerve tissue.
  • nerve tissue can be treated or sealed by applying a polymer composition of the present disclosure to the lumen of nerve conduits in the location of nerve injury.
  • the present disclosure provides methods for treating a defect, injury, or disease in the nerves or CNS tissue of a subject, with the polymer compositions of the present disclosure.
  • the method includes: applying a pre-gelation polymer composition of the present disclosure (e.g., a polymer composition comprising acryloyl-substituted gelatin) to an applicator; placing the applicator containing the pre-gelation polymer composition onto a surface of the nerves or CNS tissue of the subject (e.g., nerves of the peripheral nervous system); and crosslinking (e.g., photocrosslinking) the polymer composition by exposing the pre-gelation polymer composition to a crosslinking initiator (e.g., visible light).
  • a crosslinking initiator e.g., visible light
  • the method includes removing the applicator from the gel polymer composition and/or nerves/CNS tissue surface after the polymeric crosslinking and/or gelation of the polymer composition is complete.
  • the pre-gelation polymer composition is applied directly to the surface of the target nerves or CNS tissue without an applicator.
  • the pre- gelation polymer composition can have a strong, sustained adhesion and high retention on the target nerves or CNS tissue of the subject.
  • the gel polymer composition can have a strong, sustained adhesion and high retention on the target nerves or CNS tissue of the subject.
  • the polymer composition is engineered to present physical, mechanical, structural, chemical and/or biological properties (elasticity, water content) to match or resemble the target nerves or CNS tissue (e.g., nerves of the peripheral nervous system).
  • the polymer compositions of the present disclosure can include the polymeric or therapeutic components, or can be produced, analyzed or used by the methods (including for the treatment of nerve injuries) as disclosed in US 20190070338, which is incorporated herein by reference in its entirety, insofar as it describes the composition, production, analysis and use of acrylated gelatin polymeric compositions, such as GelMA hydrogels.
  • polymer compositions of the present disclosure can be used as a sealant and/or therapeutic composition for treating and/or repairing soft tissue in the cardiovascular system (e.g., heart) of a subject.
  • polymer compositions can be used for treating and/or repairing cardiovascular tissue associated with traumatic injury or surgical damage, including cardiac tissue. Typical surgical interventions for these ailments (including suturing and/or commercial adhesives) are often associated with inflammation and infection, scaring, slower tissue regeneration, or loss of function (partial or complete).
  • vascular/cardiovascular tissue can be treated or sealed by applying a polymer composition of the present disclosure to the target vascular/cardiovascular tissue.
  • vascular/cardiovascular tissue can be treated or sealed by applying a cell-laden hydrogel composition of the present disclosure to the target vascular/cardiovascular tissue.
  • a cell-laden hydrogel composition comprises cells or cellular precursors which encourage or facilitate the repair, restoration, replacement, or regeneration of vascular/cardiovascular tissue (e.g., cardiac tissue).
  • a cell-laden hydrogel composition comprises one or more cells or cellular precursors selected from: smooth muscle cells, cardiomyocytes, fibroblasts, mesenchymal stem cells, bone marrow stem cells, or a combination thereof.
  • the cell-laden hydrogel composition is in the form of a mat, fabric, mesh, or other shape which is amenable to being used as a covering or transplant.
  • the present disclosure provides methods for treating a defect, injury, or disease in the cardiovascular tissue of a subject, with the polymer compositions of the present disclosure.
  • the method includes: applying a pre-gelation polymer composition of the present disclosure (e.g., a polymer composition comprising acryloyl-substituted gelatin) to an applicator; placing the applicator containing the pre-gelation polymer composition onto a surface of the cardiovascular tissue of the subject (e.g., heart tissue); and crosslinking (e.g., photo-crosslinking) the polymer composition by exposing the pre-gelation polymer composition to a crosslinking initiator (e.g., visible light).
  • a pre-gelation polymer composition of the present disclosure e.g., a polymer composition comprising acryloyl-substituted gelatin
  • crosslinking e.g., photo-crosslinking
  • the method includes removing the applicator from the gel polymer composition and/or cardiovascular tissue surface after the polymeric crosslinking and/or gelation of the polymer composition is complete.
  • the pre-gelation polymer composition is applied directly to the surface of the target cardiovascular tissue without an applicator.
  • the pre-gelation polymer composition can have a strong, sustained adhesion and high retention on the cardiovascular tissue of the subject.
  • the gel polymer composition can have a strong, sustained adhesion and high retention on the cardiovascular tissue of the subject.
  • the polymer composition is engineered to present physical, mechanical, structural, chemical and/or biological properties (elasticity, water content) to match or resemble the target cardiovascular tissue (e.g., heart tissue).
  • the polymer compositions of the present disclosure can include the polymeric or therapeutic components, or can be produced, analyzed or used by the methods (including for the treatment of cardiovascular injuries) as disclosed in WO 2014063194, which is incorporated herein by reference in its entirety, insofar as it describes the composition, production, analysis and use of acrylated gelatin polymeric compositions, such as GelMA hydrogels.
  • polymer compositions of the present disclosure can be used as a sealant and/or therapeutic composition for treating and/or repairing soft tissue in the lungs of a subject.
  • polymer compositions can be used for treating and/or repairing lung tissue associated with traumatic injury or surgical damage. Typical surgical interventions for these ailments (including suturing and/or commercial adhesives) are often associated with inflammation and infection, scaring, slower tissue regeneration, or loss of function (partial or complete).
  • lung tissue can be treated or sealed by applying a polymer composition of the present disclosure to the target lung tissue.
  • lung tissue can be treated or sealed by applying a cell-laden hydrogel composition of the present disclosure to the target lung tissue.
  • a cell-laden hydrogel composition comprises cells or cellular precursors which encourage or facilitate the repair, restoration, replacement, or regeneration of lung tissue.
  • the cellladen hydrogel composition is in the form of a mat, fabric, mesh, or other shape which is amenable to being used as a covering or transplant.
  • the present disclosure provides methods for treating a defect, injury, or disease in the lung tissue of a subject, with the polymer compositions of the present disclosure.
  • the method includes: applying a pre-gelation polymer composition of the present disclosure (e.g., a polymer composition comprising acryloyl-substituted gelatin) to an applicator; placing the applicator containing the pregelation polymer composition onto a surface of the lung tissue of the subject; and crosslinking (e.g., photo-crosslinking) the polymer composition by exposing the pre-gelation polymer composition to a crosslinking initiator (e.g., visible light).
  • a pre-gelation polymer composition of the present disclosure e.g., a polymer composition comprising acryloyl-substituted gelatin
  • crosslinking e.g., photo-crosslinking
  • the method includes removing the applicator from the gel polymer composition and/or lung tissue surface after the polymeric crosslinking and/or gelation of the polymer composition is complete.
  • the pre-gelation polymer composition is applied directly to the surface of the target lung tissue without an applicator.
  • the pre- gelation polymer composition can have a strong, sustained adhesion and high retention on the lung tissue of the subject.
  • the gel polymer composition can have a strong, sustained adhesion and high retention on the lung tissue of the subject.
  • the polymer composition is engineered to present physical, mechanical, structural, chemical and/or biological properties (elasticity, water content) to match or resemble the target lung tissue.
  • Administering refers to providing a composition to a subject.
  • Amelioration refers to a lessening of severity of at least one indicator of a condition or disease.
  • animal refers to any member of the animal kingdom. In certain embodiments, “animal” refers to humans at any stage of development. In certain embodiments, “animal” refers to non-human animals at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig). In certain embodiments, animals comprise, but are not limited to, mammals, birds, reptiles, amphibians, fish, and worms. In certain embodiments, the animal is a transgenic animal, genetically engineered animal, or a clone.
  • “linked,” “attached,” and “tethered,” when used with respect to two or more moieties, means that the moieties are physically associated or connected with one another, either directly or via one or more additional moieties that serves as a linking agent, to form a structure that is sufficiently stable so that the moieties remain physically associated under the conditions in which the structure is used, e.g., physiological conditions.
  • An “association” need not be strictly through direct covalent chemical bonding. It may also suggest ionic or hydrogen bonding or a hybridization-based connectivity sufficiently stable such that the “associated” entities remain physically associated.
  • Biocompatible refers to a material which produces minimal or zero toxic, injurious, or immunological response in living tissue.
  • Biodegradable' refers to a material which can decompose partially or fully under physiological conditions into biologically processable byproducts. For example, a material can be considered biodegradable if at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the material can decompose under physiological conditions within a desired period of time (e.g., minutes, hours, days, weeks, or months, depending on the nature of the material and physiological application).
  • biodegradable can encompass the term “bioresorbable,” which describes a substance that decomposes under physiological conditions, breaking down to products that undergo bioresorption into the host subject (e.g., as metabolites of biochemical systems).
  • biologically active refers to a characteristic of any substance or material that has activity in a biological system and/or organism. For instance, a material that, when administered to an organism, has a biological effect on that organism, is considered to be biologically active.
  • Compounds of the present disclosure comprise all of the isotopes of the atoms occurring in the intermediate or final compounds. “Isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen comprise tritium and deuterium.
  • the compounds and salts of the present disclosure can be prepared in combination with solvent or water molecules to form solvates and hydrates by routine methods.
  • Cross-link As used herein, the terms “cross-link” or “cross-linking” refer bond formation (e.g., covalent bond formation) that links one polymer unit to another polymer unit.
  • Direct Action of the Cells' As used herein, the term “the direct action of the cells” means that the transplanted cells directly produce therapeutic molecules or directly treat structural defects leading to disease modification. For example, islet cells produce insulin, cardiomyocytes (cardiac muscle cells) contract the heart, and photoreceptors cells respond to light.
  • Encapsulate As used herein, the term “encapsulate” means to enclose, surround or encase.
  • Engineered As used herein, embodiments of the present disclosure are “engineered” when they are designed to have a feature or property, whether structural or chemical, that varies from a starting point or native molecule.
  • Effective Amount As used herein, the term “effective amount” of an agent is an amount sufficient to effect beneficial or desired results, for example, clinical results, and, as such, an effective amount depends upon the context in which it is being applied. For example, in the context of administering an agent that treats an ocular trauma or disorder, an effective amount of an agent is, for example, an amount sufficient to achieve treatment of the ocular trauma or disorder, as compared to the response obtained without administration of the agent.
  • Feature As used herein, a “feature” refers to a characteristic, a property, or a distinctive element.
  • zzz vitro refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, in a Petri dish, etc., rather than within an organism (e.g., animal, plant, or microbe).
  • zzz vivo refers to events that occur within an organism (e.g., animal, plant, or microbe or cell or tissue thereof).
  • Modified refers to a changed state or structure of a molecule of the present disclosure. Molecules may be modified in many ways comprising chemically, structurally, and functionally. As used herein, embodiments of the disclosure are modified when they have or possess a feature or property, whether structural or chemical, that varies from a starting point or native molecule.
  • Non-human animal includes all animals (e.g., vertebrates) except Homo sapiens, including wild and domesticated species.
  • non-human vertebrate animals include, but are not limited to, mammals, such as alpaca, banteng, bison, camel, cat, cattle, deer, dog, donkey, gayal, goat, guinea pig, horse, llama, mule, pig, rabbit, reindeer, sheep water buffalo, and yak.
  • Non-human animals include non- human primates.
  • pharmaceutically acceptable or “therapeutically acceptable” are employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • compositions described herein e.g., a vehicle capable of suspending or dissolving the polymeric compound
  • compositions described herein also comprises pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form (e.g., by reacting the free base group with a suitable organic acid).
  • examples of pharmaceutically acceptable salts comprise, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • Representative acid addition salts comprise acetate, acetic acid, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzene sulfonic acid, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, di gluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy- ethanesulfonate, 4-(2 -hydroxy ethyl)- 1 -piperazineethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesul
  • Representative alkali or alkaline earth metal salts comprise sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, comprising, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • the pharmaceutically acceptable salts of the present disclosure comprise the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile can be used.
  • Secondary Cells refers to cells that are mechanically or bimolecularly supported by the transplanted cells.
  • the transplanted cells support can improve the secondary cell’s function, which then improves symptoms or decreases or alleviates or slows disease progression.
  • An example of secondary cells supported by transplanted cells include retinal pigment epithelium (RPE), which improves photoreceptor health (the secondar cell) and lead to vision improvement.
  • RPE retinal pigment epithelium
  • Another example includes myelin producing cells, which support neurons (the secondary cell).
  • Subject' refers to any organism to which a composition in accordance with the present disclosure may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes.
  • Typical subjects comprise animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans) and/or plants.
  • the subject or patient may seek or need treatment, require treatment, is receiving treatment, will receive treatment, or is under care by a trained professional for a particular disease or condition.
  • the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest.
  • One of ordinary skill in the arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result.
  • the term “substantially” is therefore used herein to expressly capture the potential lack of completeness inherent in many biological and chemical phenomena. Likewise, the exclusion of the term “substantially” does not preclude the same potential lack of completeness inherent in many biological and chemical phenomena.
  • Synthetic means produced, prepared, and/or manufactured by the hand of man. Synthesis of polynucleotides or polypeptides or other molecules of the present disclosure may be chemical or enzymatic.
  • therapeutic agent refers to any agent that, when administered to a subject, has a therapeutic, diagnostic, and/or prophylactic effect and/or
  • therapeutic agents include, but are not limited to oligonucleotides (e.g., sense and/or antisense DNA and/or RNA), proteins and polypeptides (e.g., hormones, growth factors), small molecules and pharmaceuticals, and cells (e.g., stem cells, epithelium cells).
  • oligonucleotides e.g., sense and/or antisense DNA and/or RNA
  • proteins and polypeptides e.g., hormones, growth factors
  • small molecules and pharmaceuticals e.g., stem cells, epithelium cells.
  • Treating refers to partially or completely alleviating, ameliorating, improving, relieving, preventing, delaying onset of, inhibiting progression of, reducing severity of, and/or reducing incidence of one or more symptoms or features of a particular infection, disease, disorder, and/or condition.
  • Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition and/or to a subject who exhibits only early signs of a disease, disorder, and/or condition for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.
  • articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that comprise “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.
  • the present disclosure can include embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process.
  • the present disclosure can include embodiments in which more than one, or the entire group members are present in, employed in, or otherwise relevant to a given product or process.
  • any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the compositions of the present disclosure (e.g., any antibiotic, therapeutic or active ingredient; any method of production; any method of use; etc.) can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art.
  • GelMA precursor polymeric compositions can be synthesized as described in the art.
  • GelMA is synthesized by dissolving 10% (w/v) gelatin (e.g., porcine gelatin) in phosphate-buff ered saline (PBS), and then heated at 60°C for 20 minutes. The heating is followed by dropwise addition of 8% (v/v) methacrylic anhydride at 50°C for 3 hours (under continuous stirring), followed by dilution with PBS and dialysis at 40-50°C for about 7 days (using deionized water). The resulting mixture is filtered and lyophilized for 4 days.
  • the resulting GelMA precursor polymeric composition can be stored at -80°C until further use.
  • GelMA is synthesized by dissolving 10 grams of gelatin from fish skin in 100 ml DPBS at 60°C for 30 minutes. 8% (v/v) methacrylic anhydride is then added to the solution dropwise under stirring at 60°C for 3 hours. An additional 300 ml DPBS is added to halt the reaction. The resulting mixture is dialyzed using a deionized water bath at 50°C for about 5 days to remove the unreacted methacrylic anhydride. The resulting solution is filtered and lyophilized for about 4 days.
  • Hydrogel polymeric compositions can be synthesized as described in the art.
  • a freeze-dried GelMA precursor polymeric composition produced according to Example 1 is dissolved in PBS or (4-(2 -hydroxy ethyl)- 1 -piperazineethanesulfonic acid) buffered saline at concentrations of 5-25% (w/v).
  • Either 2-hydroxy-4’-(2- hydroxy ethoxy)-2- methylpropiophenone or Eosin Y or Eosin Y disodium salt is added as a photoinitiator, and the mixture is dissolved at 20-80 °C.
  • the amount of each element added is based on the desired physical, mechanical, structural, chemical and/or biological properties of the hydrogel polymeric composition.
  • the resulting precursor polymeric composition is photocrosslinked via visible light irradiation (e.g., blue or white light) to form a GelMA hydrogel polymeric composition.
  • a GelMA hydrogel polymeric composition is synthesized by first dissolving 7-15% w/v of gelatin methacryloyl from Example 1 into a solution containing at least one photoinitiator element, such as a mixture of triethanolamine (about 2% w/v) and N-vinyl caprolactam (about 1.25% w/v), in distilled water at room temperature. A solution of Eosin Y disodium salt (0.5 mM) is then added to the gelatin methacryloyl solution, and the resulting precursor polymeric composition is then photocrosslinked under exposure to visible light (420-480 nm) for 120 seconds.
  • at least one photoinitiator element such as a mixture of triethanolamine (about 2% w/v) and N-vinyl caprolactam (about 1.25% w/v)
  • microparticles e.g., micelles
  • a therapeutic agent e.g., ocular antibiotic such as ciprofloxacin
  • Porosity can be measured and analyzed by fabricating a freeze-dried, gold-sputter- coated hydrogel sample, which can then be imaged using a scanning electron microscope (SEM).
  • SEM scanning electron microscope
  • Samples can also be subjected to a range of mechanical tests, including elasticity, swelling, compression testing, texture, and tensile testing.
  • a GelMA hydrogel polymeric composition is formed on the surface of a target tissue. Resulting samples can be subjected to a range of mechanical and therapeutic tests, including adhesion, burst pressure, wound closure strength, shear strength, and durability/degradation rate.
  • Hydrogel polymeric compositions were prepared according to the follow steps.
  • a photopolymerization initiator mixture was prepared comprising: 0.35 mg/mL of eosin Y (20% v/v), 12.5 mg/mL N-vinylcaprolactam, and 18.75 mg/mL triethanolamine (80% v/v), in phosphate buffer saline (PBS; pH 7), with pH adjustment using concentrated HC1 as needed.
  • PBS phosphate buffer saline
  • GelMA precursor materials (when applicable for a target formulation) were then added at the desired concentration (e.g., 4-20% w/v) into the hydrogel precursor mixture, and allowed to dissolve at 60°C for about 2 hours with occasional vortexing.
  • desired concentration e.g. 4-20% w/v
  • a therapeuticagent when applicable for a target formulation was added at the desired concentration (e.g., 1-350 mg/mL). The mixture was maintained under stirring at 37°C until ready for polymerization.
  • Hydrogel disk samples were prepared by pipetting about 100 pL of hydrogel precursor mixture into individual poly(dimethyl siloxane) (PDMS) cylindrical molds positioned in wells of a 24-well non-treated plate.
  • the polymer composition was then photocrosslinked using a Dolan-Jenner high-intensity LED illuminator (MI-LED-US-B1) equipped with a dual-arm gooseneck configuration (one arm above and one arm below, thus allowing for dual light exposure from top and bottom; incident ray 90°).
  • MI-LED-US-B1 Dolan-Jenner high-intensity LED illuminator
  • Hydrogel rod samples were prepared by dipping 0.75 mm inner-diameter borosilicate glass capillaries into the hydrogel precursor mixture, and then oscillating the capillary tubes until filled up to about 10 mm from the opening.
  • PET transwell inserts (0.4 pm pore size) were then incubated in serum containing endothelial growth media for 15 minutes.
  • the inserts were dried with eye spears and 13.2 pL of each hydrogel precursor solution (containing HUVECs) was added to individual transwell undersides and exposed to 1 min of high intensity white light (Dolan-Jenner high-intensity LED illuminator MI-LED-US-B1 equipped with a dual -arm gooseneck configuration).
  • the transwells were then inverted onto well plates, such that the hydrogels on each transwell underside were submerged in endothelial growth media supplemented with growth factors and serum.
  • Free HUVECs i.e., non-hydrogel encapsulated cells
  • Free HUVECs were also added to endothelial growth media in the well plates as a control.
  • Cell growth for each formulation was analyzed on after several days (e.g., Day 4 and Day 11) using GFP+ imaging, and using confocal imaging on Day 11.
  • GFP+ Imaging Results were also added to endothelial growth media in the well plates as a control. Cell growth for each formulation was analyzed on after several days (e.g., Day 4 and Day 11) using GFP+ imaging, and using confocal imaging on Day 11.
  • hydrogel sample for G5(80) from Example 4(a) was stained for the following: Actin (cytoskeleton showing cell spreading and network formation);
  • FIG. 5 A and FIG. 5B including formation of a dense cellular network with good cell distribution and no evidence of cell clumping.
  • Free cell (i.e., no hydrogel) control samples showed lower cell density and poor network formation (FIG. 5C) when compared to G5(80) samples.
  • Study results showed that HUVECs spread more effectively, created stronger cellular networks, and aggregated less within GelMA-based formulations, as compared to PEGDA-based formulations. Study results also showed that higher crosslinking densities (e.g., higher polymer concentration, higher DOM) generally did not promote for strong cell spreading and network formation. GelMA-based materials also provided stronger adhesion to the test surface (i.e., transwell undersurface) and deposit cells more effectively to form a dense cell network, even in challenging environments and growth conditions (e.g., against gravity).
  • HRPEC Human Retinal Pigment Epithelium Cells
  • PET transwell inserts (0.4 pm pore size) were then incubated in serum containing DMEM/F-12 media (supplemented with 10% FBS) for 15 minutes. The inserts were dried with eye spears and 13.2 pL of each hydrogel precursor solution (containing HRPECs) was added to individual transwell undersides and exposed to 1 min of light. The transwells were then inverted onto well plates, such that the hydrogels on each transwell underside were submerged in DMEM/F-12 media (supplemented with 10% FBS). Cell growth for each formulation was imaged and analyzed after several days (e.g., Day 3, Day 8, Day 10, Day 20), which included the use of Calcein AM staining and imaging.
  • HRPECs have minimal spread and networking within hydrogel formulations that have a high degree of methacrylation, a high molecular weight, and/or a high polymer concentration of hydrogels. HRPECs had improved spread and networking within hydrogel formulations that had a lower degree of methacrylation and lower polymer concentration of hydrogels, thus allowing for effective HRPEC deposition and monolayer formation.
  • PEG-based hydrogels such as PEGDA were generally shown to have poor bioadhesion and poor biodegradability (often being detached from underneath transwells in as little as 24-48 hours, see Table 3). Remaining HRPECs on the transwell surface were believed to be those that were trapped on the surface of the PEGDA hydrogel during the photopolymerization process. Cells were not able to attach or migrate through the PEGDA polymeric network, remaining trapped and only able to attach to neighboring cells.
  • HRPEC Human Retinal Pigment Epithelium Cells
  • PET transwell inserts (0.4 pm pore size) were then incubated in serum containing DMEM/F-12 media (supplemented with 10% FBS) for 15 minutes. The inserts were dried with eye spears and about 10 pL of each hydrogel precursor solution (containing HRPECs) was added to individual transwell topsides and exposed to 1 min of light. The transwells were then submerged in DMEM/F-12 media (supplemented with 10% FBS). Free HRPECs (i.e., no hydrogel) were also added to media in the well plates as a control.
  • FIG. 8A Cell-only control samples showed uninhibited cell growth and monolayer formation.
  • G5(10) samples showed hydrogels beginning to degrade, depositing HRPECs, and beginning to form monolayer networks.
  • G5(80) samples showed no hydrogel degradation and no monolayer formation, with cells generally remaining rounded and suspended within the hydrogel.
  • FIG. 8B Cell-only control samples continued to show uninhibited cell growth and monolayer formation, with cells showing dense packing.
  • G5(10) samples showed hydrogels mostly degraded, with deposited HRPECs forming a clear monolayer network similar to the control sample at 24 hours, and with few rounded, encapsulated cells remaining over the monolayer.
  • G5(80) samples continued to show little hydrogel degradation and little monolayer formation, with cells generally remaining rounded and suspended within the hydrogel.
  • FIG. 8C Cell-only control samples continued to show uninhibited cell growth and monolayer formation, with packed cell density and networking.
  • G5(10) samples showed degraded hydrogels, with a deposited HRPECs monolayer network similar in density and morphology to the control sample, and with few rounded cells remaining over the monolayer.
  • G5(80) samples showed hydrogels beginning to degrade and early monolayer formation in certain regions (top right of FIG. 8C image for G5(80)), while other regions remained undegraded with no monolayer formation (lower left of FIG. 8C image for G5(80)), and with HRPECs remaining rounded and suspended within the hydrogel.
  • each formulation was injected (in PBS) through a MedOne Subretinal PolyTip® 38G (outer diameter) (41G inner diameter) subretinal cannula (with a standard 1 mL luer-lok plastic syringe) at a controlled rate of 200- 300 pL/min (flow rate controlled with a syringe pump) onto 6-well transwell plates with 0.4 pm polyester (polyethylene terephthalate) membranes.
  • the polyester membranes were included to mimic a native Bruch's membrane; membrane is permeable to nutrients and proteins, but not to cells.
  • the injected formulations were then photo crosslinked in 10 pL drops using white light.
  • Precursor formulations from Example 7A were prepared at ⁇ 1 million cells/mL, and then injected (in PBS) onto 6-well transwell plates with 0.4 pm polyester (polyethylene terephthalate) membranes using the same delivery system and conditions as Example 7A. The injected formulations were then photo crosslinked in 10 pL drops using white light. After one week, live-cell imaging was completed using Calcein AM. Results are shown in FIG. 9C. Study results showed that RPE cells had formed a monolayer, with cells retaining a cuboidal morphology and pigmentation patterns that are characteristics of standard, healthy RPE morphology. The RPE cells delivered in the saline (control) formulation became elongated and highly proliferative, and failed to retain their cuboidal morphology and RPE pigmentation patterns indicating de-differentiation.
  • a G5(10) [5% GelMA, 10% DoM] hydrogel precursor formulation was prepared according to the general procedures in Example 3, with reduced concentrations of photopolymerization initiator mixture.
  • the formulations were then injected (in PBS) onto RPE monolayers in 6-well transwell plates with 0.4 pm polyester (polyethylene terephthalate) membranes, using the same delivery system and conditions as Example 7 A.
  • the injected formulations were then photo crosslinked using white light.
  • RPE retinal pigment epithelial cells
  • SR subretinal
  • test groups included 200 pl injections into 6 eyes (for each group, 24 eyes and 12 animals total):
  • Blocks were sectioned sagittally (14 pm) at 5 levels across the eye: nasal, peripheral, midway between nasal and optic nerve head (ONH), ONH, midway between the ONH and temporal, and temporal peripheral. At least 10 slides/level were collected. Slides were scanned during acquisition for the cell depot. A series of 8-10 slides/eye was selected for IHC.
  • Results of observations related to cell migration to retina surface are shown in FIG. 10 A.
  • the saline control formulations exhibited more cell migration (above 80%) and corresponding epiretinal adverse events due to poor cell localization (i.e., cells outside of subretinal area). This finding was confirmed by histological examination of the eye after day 28, in which vitreous cells were found, and subretinal hydrogel formulations exhibited minimal cell migrations of about 20% or below.
  • FIG. 10B Results of observations related to hydrogel degradation after 28 days are shown in FIG. 10B.
  • the Group 1 did not include hydrogel.
  • Group 2 only about 33% of hydrogel remained after 28 days (i.e., about 67% lost).
  • Group 3 and Group 4 had about 100% hydrogel remaining after 28 days (i.e., about 0% lost).
  • hydrogels with high 80% methacrylation (Group 3 and Group 4) showed retinal detachment from underlying layers, as seen in FIG. 10C and FIG. 10D.
  • Staining results did show successful human stem cell transplant onto native pig RPE layers, which were not disrupted (see FIG. 10E, wherein the arrows represent human cells).
  • Rxn 3 was further studied. 10 M cells/mL were added to each of Rxn 3 and PBS (as control). The Rxn 3 sample and a portion of the PBS control were extruded onto a transwell surface, as well as unextruded PBS. After two weeks, Rxn 3 showed a healthy RPE monolayer growth, similar to the PBS controls, with the Rxn 3 sample providing a high cell count than either PBS control sample. Cell count results are show in FIG. 11.
  • RPE retinal pigment epithelial cells
  • SR subretinal
  • test groups included 50 pl injections into 6 eyes (gel formulations) or 3 eyes (saline control) - 15 eyes total
  • H&E hematoxylin and eosin
  • IHC Immunohistochemistry
  • RPE retinal pigment epithelial cells
  • RPE retinal pigment epithelial cells
  • Samples of G5(90/60) gel precursor formulations were prepared.
  • the G5(90/60) samples were then seeded with one of the following RPE cell concentrations: 5 million cells/mL, 10 million cells/mL, 15 million cells/mL, 20 million cells/mL, or 30 million cells/mL, PBS samples were prepared with the same cell concentrations. Samples were extruded/injected though subretinal cannula onto plates and allowed to grow for up to 8 weeks. Results are shown in FIG. 14A to FIG. 14E.
  • FIG. 14A shows cell growth results for a 5 million (M) cells/mL concentration. After 8 weeks of growth, the 5 M/mL cell density with hydrogel formulation resulted in poor surface area coverage and epithelial to mesenchymal transition (EMT), leaving notable gaps in the cell layer. The corresponding PBS injected cells at 5 M/mL was able to form monolayers over time.
  • FIG. 14B shows cell growth results for a 30 million (M) cells/mL concentration for 8 weeks. After 8 weeks of growth, both the hydrogel formulation and PBS control at 30 M/mL cell density showed notable gaps in the cell layer. The tight cell packing likely resulted in high stress conditions that bulged cells groups and created the noted gaps in the mature cell monolayer.
  • FIG. 14C shows cell growth results for a 20 million (M) cells/mL concentration at 3 days, 7 days, and 12 days.
  • M 20 million
  • the 20 M/mL cell density showed notable cell clumps in the monolayer, and a high dead cell count after 7 days due to high number of cells that are unable to attach to surface of plate.
  • a cell monolayer had formed from the remaining cells.
  • the 20 M/mL cell density did form a monolayer after 12 days of growth, the high dead cell count at day 7 would not be ideal for in vivo injections.
  • FIG. 14D shows cell growth results for a 10 million (M) cells/mL concentration at 3 days, 7 days, 12 days, and 8 weeks (56 days). Cell adhesion and growth was shown to be healthy at 3 days, 7 days, and 12 days. After 8 weeks, a healthy cell monolayer remained.
  • M 10 million
  • FIG. 14E shows cell growth results for a 15 million (M) cells/mL concentration at 3 days, 7 days, 12 days, and 8 weeks (56 days). Cell adhesion and growth was shown to be healthy at 3 days, 7 days, and 12 days. After 8 weeks, a healthy cell monolayer remained.
  • FIG. 15 shows imaging of cell flow through glass needle for PBS and G5(90/60) samples. While cells in the PBS sample showed clear clumping and sticking during the injection (resulting from shear stress across the cannula), cells in the G5(90/60) samples flowed effectively through the needle (resulting from shear stress concentrated at the canular wall) without clumping for absorption to the needle inner surface.
  • test article saline, RPE cells in saline suspension, or RPE cells in the GelMA polymer composition
  • the polymer composition test article was crosslinked via 60s of light exposure from the light pipe at 80-100% intensity.
  • a baseline and weekly dark-adapted full field electroretinography (ffERG) were performed to assess electrical activity within the retina.
  • the dark-adapted (scotopic) waveform from 3 cd s m’ 2 light exposure was analyzed for the B wave amplitude, representing photoreceptor activity. Measuring the decrease from baseline levels demonstrated rapid loss of vision followed by stable vision in treated animals and continued decline in the control group.
  • OCT optical coherence tomography
  • Induced pluripotent stem cell (iPSC)-derived retinal pigment epithelial (RPE) cells were harvested and mixed with the GelMA polymer composition using aseptic technique and sterile reagents.
  • the hydrogel formulation was a methacrylate functionalized gelatin polymer that upon light activation crosslinks, encapsulates and localizes the cells to the target tissue.
  • the following groups were tested:
  • a 30 mg/mL solution of NalOs in sterile 0.9% NaCl was prepared within 24 hours of administration to degenerate the RPE of the animal.
  • animals were manually restrained and a thin layer of 5% lidocaine ointment was applied topically to the skin overlying the marginal ear vein prior to needle insertion.
  • Wintergreen oil was also applied to facilitate vasodilation as needed.
  • 1 mL/kg of the NalCE solution was slowly delivered intravenously.
  • 50 mL of lactated Ringer’s solution was also administered subcutaneously (SQ) to reduce the risk of adverse renal effects. Animals were returned to their cage and monitored briefly.
  • test article either the RPE cells in suspension or in polymer composition
  • test article either the RPE cells in suspension or in polymer composition
  • an extendible PolyTip® subretinal injection cannula 25G x 28 mm cannula with 38G (5 mm length) tip
  • extendible Poly Vent® subretinal injection cannula 25G x 32 mm cannula with 38G (5 mm length) tip
  • the MedOne polymeric tip was extended, and the needle primed with approximately 240 pL (PolyTip) or 100 pL (Poly Vent) of test material.
  • the needle and syringe pair were allowed to rest on an even surface for one minute as the pressure throughout the system equilibrated. Thereafter, the polymeric tip was wiped for excess solution utilizing sterile gauze followed by an additional 30 seconds of dwell time. The polymeric tip was then retracted, and the needle and syringe pair moved to the surgical field. The needle and syringe pair remained horizontal and in the same plane prior to injection.
  • the MicroDose Injector was attached to a Viscous Fluid Control Pak (when available) to allow foot pedal-actuated injections at a controlled rate via the Constellation system. Care was taken to avoid excessively kinking or twisting the extension tubing to avoid creating pressure and cause material to drool from the tip. If solution was observed at the needle tip prior to injection, it was carefully wiped with sterile gauze.
  • the PSI was set to 9-30 (lower end for saline, higher end for polymer).
  • 30 pL of the prepared test article was injected subretinally at a rate of approximately 30 pL/15-20 seconds, and time at injection was recorded.
  • the needle was held in place for at least 5 seconds, followed by the immediate application of high intensity light utilizing the vitrectomy setup light pipe (set to maximum intensity and focused in close proximity to the bleb) for at least 1 minute. This crosslinked the test articles containing hydrogel.
  • the needle was then retracted, excess material in the tubing was collected, and the needle/tubing was discarded. The conjunctiva was closed with suture.
  • Neomycin and polymyxin b sulfates and dexamethasone topical solution was topically applied to the eye, then the procedures was repeated on the contralateral eye. A new needle/tubing and syringe was utilized for each eye injection. OCT confirmatory images were taken following dosing of both eyes.
  • buprenorphine HC1 was utilized for surgery rather than buprenorphine ER, an additional dose (0.01-0.05 mg/kg, SQ) was administered in the afternoon or evening of surgery, and additional dose(s) were administered the following day if needed based on assessment by veterinary staff.
  • Procedure All activities and recording for the ERG procedure were performed under dim red lighting. Before ERGs were recorded, pupils were checked to ensure adequate dilation. Diagnosys ERG systems was utilized for measurements. Animals were positioned on the first ERG machine atop a warm pad, then 0.5% proparacaine and eye lubricant were applied to the eyes, followed by the electrode contact and reference leads. A reference subcutaneous lead was placed in the head and a ground lead placed near the tail of the animal. ERG parameters were as follows:
  • Step 1-9 Each step advanced half log units in light intensity, from 0.001-10 cd s m' 2 scotopic ERG. Both ERG traces and oscillatory potentials were collected (where applicable: a-wave, b-wave, c-wave).
  • Step 10 Dark-adapted 150 cd s m' 2 scotopic traces and oscillatory potentials were collected (where applicable: a-wave, b-wave, c-wave).
  • Post-Procedural Care Following the procedure, animals either proceeded to OCT/fundus imaging, received atipamezole (1-2 mg/kg, IM) to reverse the effects of dexmedetomidine and were returned to their cages for recovery, or were euthanized at the final timepoint. If needed to aid in recovery, animals also received 40-60 mL warmed lactated Ringer’s solution SQ, when necessary.
  • Procedure Animals underwent OCT imaging procedures of the posterior section of the eye. If needed, a wire eyelid speculum was placed and 0.5% proparacaine HC1 was applied topically to the eye. Using the Heidelberg Spectralis OCT, a series of b-scans was acquired inferior (corresponding to the test article injection location), superior, temporal, and nasal to the optic nerve head. Following b-scan acquisition, en face BAF images was collected.
  • Post-Procedural Care Following the procedure, animals either proceeded to fundus imaging, received atipamezole (1-2 mg/kg, IM) to reverse the effects of dexmedetomidine and were returned to their cages for recovery, or were euthanized at the final timepoint. If needed to aid in recovery, animals also received 40-60 mL warmed lactated Ringer’s solution SQ.
  • mice were sedated with ketamine/dexmedetomidine (10- 15/0.1-0.2 mg/kg, IM), or remained sedated following final imaging collection, and euthanasia was performed with an overdose of sodium pentobarbital administered IC or IV, followed by auscultation or palpation to ensure death.
  • Table 5 presents conditions the eye cups collected from designated animals subjected in preparation for RPE/Choroid flatmounting and imaging.
  • Table 5 RPE/Choroid Flatmounting buffer. Using a #11 scalpel, 4-5 incisions were made around the RPE/choroid for flatmounting. An imaging spacer or vacuum grease was used to create a chamber on the slide. Mounting media (90% glycerol, 0.5% N-propyl gallate, 20 mM Tris pH 8; 3-4 drops) was applied within the spacer/chamber using a 2 mL transfer pipette. The slide was then coverslipped and stored at 4°C until shipment for analysis. Results from the study described in Example 13(a) are shown in FIG. 16C, showing a dense monolayer formation with GelMA formulation (top), whereas the suspension formulation showed little monolayer formation (bottom).
  • Example 13(a) results from the study described in Example 13(a) are shown in FIG. 16D.
  • the cell suspension formulation showed disorganized photoreceptors and loss of axons and out segments, with the GelMA formulation showed a preserved three- layer construct of photoreceptor structure.
  • the ONL thickness in the GelMA formulation was also about 10 pm greater than the suspension formulation.
  • eyes designated for cryosectioning were enucleated and marked with a metallic sharpie superiorly at the 12 o’clock position. An approximately 3 mm incision was made at the limbus and the eye was placed in 4% paraformaldehyde (PF A) in phosphate-buffered saline (PBS) for 24 hours at room temperature or 48 hours at 4 °C. The anterior segment and lens were dissected away, and vitreous humor was gently removed. Eyes were cryoprotected in a gradient of sucrose (5- 30%) and embedded in OCT such that the optic nerve was facing down/anterior segment opening was up; nasal and temporal orientation were tracked.
  • PF A paraformaldehyde
  • PBS phosphate-buffered saline
  • Retinal pigment epithelial (RPE) cells at a concentration of IxlO 6 were suspended in either 1% GelMA (160/10) + 2.5% GelMA (90/60) (GelMEDIX), saline (Suspension), gelatin + hyaluronic acid (Gelatin + HA), or hyaluronic acid (Polysaccharide). Thereafter, all solutions were injected through a MedOne PolyTip Cannula (27G x 32mm cannula with 38G (0.12mm) x 5mm tip (41G inner diameter)) at a controlled flow rate of 100 L/min.
  • RPE Retinal pigment epithelial
  • calcein AM live cell marker
  • propidium iodide dead cell marker
  • Results of the test are shown in FIG. 17A. Results were as follows: (i) GelMA Formulation — about 75-80% living cells, about 20-25% dead cells, about 0% cells absorbed to needle; (ii) Suspension Formulation - about 30-35% living cells, about 15-20% dead cells, about 45-50% cells absorbed to needle; (iii) Gelatin + HA Formulation — about 55-60% dead cells, about 35-40% cells absorbed to needle; and (iv) HA Polysacharide Formulation — about 30-35% living cells, about 5-10% dead cells, about 55-60% cells absorbed to needle.
  • the RPE cells encapsulated in GMPMIX can degrade the hydrogel and form a monolayer, as shown in FIG. 17C.

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Abstract

La présente divulgation concerne des compositions de polymères améliorées, telles que des compositions polymères de gélatine acryliques. Dans certains modes de réalisation, les compositions de polymères améliorées peuvent être utilisées pour délivrer un ou plusieurs agents thérapeutiques, tels que des cellules, à une zone thérapeutique cible, telle que l'œil d'un sujet. Dans certains modes de réalisation, les compositions de polymères améliorées sont des hydrogels qui comprennent de la gélatine acrylique (par exemple, GelMA, GelAC, GelGA, GelGMA) ou leurs dérivés réticulés par polymérisation.
PCT/US2024/051735 2023-10-18 2024-10-17 Compositions de polymères de gélatine acryliques comprenant des cellules Pending WO2025085609A1 (fr)

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